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Sun Y, Qu Y, Yang Z, Lv B, Wang G, Fan K, Wang Y, Pan J, Du Z, Yu Y. Suppressed intestinal secondary bile acids in moxifloxacin-induced hyperglycemia: studies in normal and diabetic GK rats. Front Pharmacol 2025; 16:1569856. [PMID: 40255568 PMCID: PMC12006139 DOI: 10.3389/fphar.2025.1569856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Accepted: 03/19/2025] [Indexed: 04/22/2025] Open
Abstract
Objective Moxifloxacin (MFLX) frequently induces dysglycemia when used in the treatment of infectious diseases, particularly in patients with diabetes. However, the mechanism through which MFLX affects host glucose metabolism remains unclear. This study aimed to investigate the possible mechanism underlying MFLX-induced hyperglycemia. Methods In this study, we investigated the short-term (3 days) and long-term (14 days) effects of MFLX on glucose metabolism in normal and type 2 diabetic GK rats. After oral administration of 40 mg/kg of MFLX, blood glucose, insulin, GLP-1, and fibroblast growth factor 15 (FGF15) levels in the blood of rats, as well as bile acids in both blood and feces, and gut microbiota, were examined. Liver and ileum tissues were promptly harvested for detecting the expression of hepatic 7α-hydroxylase (CYP7A1) and intestinal Takeda G-protein-coupled receptor 5 (TGR5) and farnesoid X receptor (FXR). In addition, we explored the effect of secondary bile acids (SBAs) on GLP-1 secretion in NCI-H716 cells, and observed the direct effect of MFLX on the expression of CYP7A1 in HepG2 cells and TGR5, FXR in NCI-H716 cells. Results It was demonstrated that MFLX induced hyperglycemia in diabetic rats, with a more pronounced reduction in serum insulin, GLP-1, and FGF15 levels than observed in normal rats. Gut microbiota associated with SBAs metabolism were significantly reduced, leading to decreased intestinal deoxycholic acid (DCA) and lithocholic acid (LCA). In vitro studies revealed that DCA and LCA (25 μM, 50 μM, and 100 μM) promoted GLP-1 secretion in a concentration-dependent manner in NCI-H716 cells. Meanwhile, we observed that the expression of intestinal TGR5 and FXR significantly downregulated, whereas CYP7A1 expression in liver was increased in GK rats after MFLX treatment. MFLX itself (0.1 μM, 1 μM, and 10 μM) did not directly altered TGR5 or FXR expressions in NCI-H716 cells, nor did it alter CYP7A1 expression in HepG2 cells, which indicated that the impact of MFLX on glucose metabolism was primarily induced by changes in bile acids metabolism resulting from alterations in the gut microbiota. Conclusion Our studies showed MFLX more likely to cause hyperglycemia when used in diabetic states and highlighted the critical role of gut microbiota-SBAs-TGR5/FXR pathway in MFLX-induced hyperglycemia.
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Affiliation(s)
- Yewen Sun
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, China
- College of Pharmaceutical Science, Soochow University, Suzhou, China
| | - Yuchen Qu
- School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Zhuan Yang
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, China
- College of Pharmaceutical Science, Soochow University, Suzhou, China
| | - Bo Lv
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Guanjun Wang
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, China
- College of Pharmaceutical Science, Soochow University, Suzhou, China
| | - Kai Fan
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yuyuan Wang
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jie Pan
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Ziyan Du
- Department of Respiration Medicine, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yunli Yu
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, China
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Bajaj P, Brennan RJ, Laurent S, Sauzeat S, Dufault M, Richards B, Adkins K. Transcriptomic analysis in liver spheroids identifies a dog-specific mechanism of hepatotoxicity for amcenestrant. Toxicol Sci 2025; 204:228-241. [PMID: 39886943 DOI: 10.1093/toxsci/kfaf012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2025] Open
Abstract
Therapeutic drugs can sometimes cause adverse effects in a nonclinical species that do not translate to other species, including human. Species-specific (rat, dog, and human) in vitro liver spheroids were employed to understand the human relevance of cholestatic liver injury observed with a selective estrogen receptor degrader (amcenestrant) in dog, but not in rat, during preclinical development. Amcenestrant showed comparable cytotoxicity in liver spheroids from all 3 species; however, its M5 metabolite (RA15400562) showed dog preferential cytotoxicity after 7 days of treatment. Whole genome transcript profiles generated from liver spheroids revealed downregulation of genes related to bile acid synthesis and transport indicative of strong farnesoid X receptor (FXR) antagonism following treatment with both amcenestrant and its M5 metabolite in the dog but not in rat or human. In human spheroids, upregulation of genes for detoxification enzymes indicative of pregnane X receptor (PXR) agonism was observed following amcenestrant treatment, whereas in the dog these genes were downregulated. The M5 metabolite showed gene dysregulation indicating PXR agonism in both rat and human, and antagonism in dog. Analysis of liver samples from a 3-mo dog toxicity study conducted with amcenestrant showed downregulation of several genes associated with PXR and FXR, corroborating the in vitro results. These results support the hypothesis that dogs are uniquely susceptible to cholestatic hepatotoxicity following administration of amcenestrant due to species-specific antagonism of FXR and highlight the value of in vitro liver spheroids to investigating mechanisms of toxicity and possible species differences.
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Affiliation(s)
- Piyush Bajaj
- Global Investigative Toxicology, Preclinical Safety, Sanofi, Cambridge, MA 02141, United States
| | - Richard J Brennan
- Global Investigative Toxicology, Preclinical Safety, Sanofi, Cambridge, MA 02141, United States
| | | | | | - Michael Dufault
- Precision Medicine and Computational Biology, Sanofi, Cambridge, MA 02141, United States
| | - Brenda Richards
- Genetic Medicine Unit, Sanofi, Waltham, MA 02451, United States
| | - Karissa Adkins
- Global Investigative Toxicology, Preclinical Safety, Sanofi, Cambridge, MA 02141, United States
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Xu J, Xue Q, Xiong A, Chen Y, Wang X, Yan X, Ruan D, Zhang Y, Wang Z, Ding L, Yang L. Chlorogenic acid attenuates pyrrolizidine alkaloid-induced liver injury through modulation of the SIRT1/FXR signaling pathway. Chin Med 2025; 20:34. [PMID: 40069808 PMCID: PMC11899315 DOI: 10.1186/s13020-025-01077-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 02/13/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Pyrrolizidine alkaloids (PAs), recognized globally for their hepatotoxic properties, significantly contribute to liver damage through an imbalance in bile acid homeostasis. Addressing this imbalance is crucial for therapeutic interventions in PA-related liver injuries. Chlorogenic acid (Cga), a phenolic compound derived from medicinal plants, has demonstrated hepato-protective effects across a spectrum of liver disorders. The specific influence and underlying mechanisms by which Cga mitigates PA-induced liver damage have not been clearly defined. MATERIALS AND METHODS To explore the protective effects of Cga against acute PA toxicity, a murine model was established. The influence of Cga on bile acid metabolism was confirmed through a variety of molecular biology techniques. These included RNA sequencing, western blotting, and immunoprecipitation, along with quantitative analyses of bile acid concentrations. RESULTS Our findings indicate that Cga enhances sirtuin 1 (SIRT1) activation and increases farnesoid X receptor (FXR) signaling, which are crucial for maintaining bile acid balance in PA-induced hepatic injury. When mice subjected to PA-induced hepatic injury were treated with SIRT1 inhibitors alongside Cga, the hepatoprotective effects of Cga were significantly reduced. In Fxr-KO mice, the ability of Cga to mitigate liver damage induced by PAs was substantially reduced, which underscores the role of the SIRT1/FXR signaling axis in mediating the protective effects of Cga. CONCLUSION Our research suggests that Cga can serve as an effective treatment for PA-mediated hepatotoxicity. It appears that influencing the SIRT1/FXR signaling pathway might provide an innovative pharmacological approach to address liver damage caused by PAs.
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Affiliation(s)
- Jie Xu
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Department of Pharmacy, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China
| | - Qiongwen Xue
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Aizhen Xiong
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yilin Chen
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xunjiang Wang
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xing Yan
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Deqing Ruan
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yumeng Zhang
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zhengtao Wang
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lili Ding
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Li Yang
- Shanghai Key Laboratory of Complex Prescriptions, The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Yang Y, Jiao L, Guo F, Sun Y, Cui H, Lei X, Hu J, Wan Y. Protein-Affinity Guided Nontargeted Analysis Reveals the Widespread FXR-Antagonistic Pollutants in Surface Water and Source Water Along the Yangtze River and Yellow River. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2025; 59:2368-2377. [PMID: 39870506 DOI: 10.1021/acs.est.4c07569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2025]
Abstract
Metabolism-disrupting chemicals (MDCs) have attracted widespread attention due to their contributions to the prevalence of metabolic diseases worldwide. The farnesoid X receptor (FXR) is a typical lipid-sensing nuclear receptor and plays a crucial role in the development of metabolic diseases. However, few studies have examined the FXR activities of environmental samples and the corresponding MDCs. In this study, we found FXR-antagonistic activities in 93.6% of source water, surface water, and wastewater samples (n = 78) collected from the Yangtze River and Yellow River. An FXR protein-affinity guided nontargeted analysis was performed and identified 79 potential FXR-active pollutants in samples from these two rivers. Nine of these pollutants exhibited strong FXR-antagonistic activities (IC50: 2.39-141.9 μM), and 6 pollutants, including triphenyl phosphate (TPHP), 4,4'-sulfonylbis[2-(2-propenyl) phenol (TGSA), tonalid (AHTN), dichlorophen, etoxazole (ETX), and loratadine, were identified to be FXR antagonists for the first time. The total concentrations of the nine FXR-antagonistic pollutants were relatively high in the middle and downstream reaches of the Yellow River and the downstream reaches of the Yangtze River, and two pollutants (TGSA and ETX) have not previously been found in aquatic environments. A risk prioritization analysis revealed that TPHP, TGSA, and AHTN are priority pollutants with the potential to affect the FXR. Appropriate management of these priority pollutants would reduce the health risks of metabolic disruptions associated with exposure to these MDCs.
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Affiliation(s)
- Yi Yang
- Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing 100871, China
| | - Ling Jiao
- Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing 100871, China
| | - Fusheng Guo
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
| | - Yibin Sun
- Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing 100871, China
| | - Hongyang Cui
- Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing 100871, China
| | - Xiaoguang Lei
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
| | - Jianying Hu
- Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing 100871, China
| | - Yi Wan
- Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing 100871, China
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Zhao M, Li G, Zhao L. The role of SIRT1-FXR signaling pathway in valproic acid induced liver injury: a quantitative targeted metabolomic evaluation in epileptic children. Front Pharmacol 2024; 15:1477619. [PMID: 39575388 PMCID: PMC11578826 DOI: 10.3389/fphar.2024.1477619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 10/23/2024] [Indexed: 11/24/2024] Open
Abstract
Aim This study aimed to gain deeper insights into the hepatotoxicity mechanisms of valproic acid (VPA), as well as to identify potential risk markers for VPA-induced hepatotoxicity. Methods Twenty-two children with epilepsy treated with VPA monotherapy were divided into a normal liver function (NLF) group, a mild abnormal liver function (ANLF1) group, and a serious abnormal liver function (ANLF2) group based on their liver function indicator levels. The full quantitative targeted metabolomics technique was used to systematically investigate how the differential endogenous metabolic components change with the development of liver injury. Results A total of 195 metabolic components were quantitatively analyzed. Nineteen identified metabolites, including five organic acids, four short-chain fatty acids, four amino acids, three fatty acids, and three benzenoids, differed significantly among the three groups, showing a strong association with VPA-induced hepatotoxicity. Only three bile acid metabolites, taurodeoxycholic acid, taurochenodeoxycholic acid, and deoxycholic acid, were significantly different between the ANLF1 and ANLF2 groups, increasing at first and then decreasing with the aggravation of liver injury. The mechanistic evaluation showed that SRT1720 activation could alleviate the severity of liver function abnormalities induced by VPA. Immunocoprecipitation indicated that VPA significantly increased the acetylation level of FXR, and the application of agonist SRT1720 can antagonize the acetylation of FXR by VPA. Conclusion Nineteen identified metabolites showed a strong association with hepatotoxicity and three bile acid metabolites changed with the development of liver injury. The SIRT1-FXR pathway was firstly proposed to participate in VPA-induced hepatotoxicity.
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Affiliation(s)
| | | | - Limei Zhao
- Department of pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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Wang T, Tian T, Zhu Z, Fang S, Zhang L, Peng X, Shi R, Li Y, Wu J, Ma Y. Gardenia jasminoides Ellis. Polysaccharides Alleviated Cholestatic Liver Injury by Increasing the Production of Butyric Acid and FXR Activation. Phytother Res 2024; 38:5363-5375. [PMID: 39237123 DOI: 10.1002/ptr.8326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 07/21/2024] [Accepted: 08/17/2024] [Indexed: 09/07/2024]
Abstract
Gardenia jasminoides Ellis. polysaccharide (GPS) can protect against cholestatic liver injury (CLI) by regulating nuclear farnesoid X receptor (FXR).However, the mechanism via which GPS mediates the FXR pathway remains unclear. The aim of this study was to investigate the mechanism. Firstly, an alpha-naphthylisothiocyanate-induced cholestatic mouse model was administered with GPS to evaluate its hepatoprotective effects. The metabolic pathways influenced by GPS in cholestatic mice were detected by serum metabolomics. The effect of GPS on bile acid (BA) homeostasis, FXR expression, and liver inflammation were investigated. Second, the intestinal bacteria metabolites affected by GPS in vivo and in vitro were determined. The activation of FXR by sodium butyrate (NaB) was measured. Finally, the effects of NaB on cholestatic mice were demonstrated. The main pathways influenced by GPS involved BA biosynthesis. GPS upregulated hepatic FXR expression, improved BA homeostasis, reduced F4/80+ and Ly6G+ positive areas in the liver, and inhibited liver inflammation in cholestatic mice. Butyric acid was the most notable intestinal bacterial metabolite following GPS intervention. NaB activated the transcriptional activity of FXR in vitro, upregulated hepatic FXR and its downstream efflux transporter expression, and ameliorated disordered BA homeostasis in CLI mice. NaB inhibited the toll-like receptor 4/nuclear factor (TLR4/NF-κB) pathway and reduced inflammation and CLI in mice. An FXR antagonist suppressed the effects. In conclusion, GPS increased butyric acid production, which can activate hepatic FXR, reverse BA homeostasis disorder, and inhibit the TLR4/NF-κB inflammatory pathway, exerting protective effects against CLI.
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Affiliation(s)
- Tianming Wang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tian Tian
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhenyun Zhu
- Analytical Research Center for Organic and Biological Molecules, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Su Fang
- Analytical Research Center for Organic and Biological Molecules, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Lincong Zhang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaotian Peng
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Rong Shi
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuanyuan Li
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiasheng Wu
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yueming Ma
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Hof WFJ, de Boer JF, Verkade HJ. Emerging drugs for the treatment of progressive familial intrahepatic cholestasis: a focus on phase II and III trials. Expert Opin Emerg Drugs 2024; 29:305-320. [PMID: 38571480 DOI: 10.1080/14728214.2024.2336986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 03/27/2024] [Indexed: 04/05/2024]
Abstract
INTRODUCTION Progressive familial intrahepatic cholestasis (PFIC) is a group of disorders characterized by inappropriate bile formation, causing hepatic accumulation of bile acids and, subsequently, liver injury. Until recently, no approved treatments were available for these patients. AREAS COVERED Recent clinical trials for PFIC treatment have focused on intestine-restricted ileal bile acid transporter (IBAT) inhibitors. These compounds aim to reduce the pool size of bile acids by interrupting their enterohepatic circulation. Other emerging treatments in the pipeline include systemic IBAT inhibitors, synthetic bile acid derivatives, compounds targeting bile acid synthesis via the FXR/FGF axis, and chaperones/potentiators that aim to enhance the residual activity of the mutated transporters. EXPERT OPINION Substantial progress has been made in drug development for PFIC patients during the last couple of years. Although data concerning long-term efficacy are as yet only scarcely available, new therapies have demonstrated robust efficacy in a considerable fraction of patients at least on the shorter term. However, a substantial fraction of PFIC patients do not respond to these novel therapies and thus still requires surgical treatment, including liver transplantation before adulthood. Hence, there is still an unmet medical need for long-term effective medical, preferably non-surgical, treatment for all PFIC patients.
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Affiliation(s)
- Willemien F J Hof
- Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
| | - Jan Freark de Boer
- Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Henkjan J Verkade
- Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
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Tsuruya K, Yokoyama K, Mishima Y, Ida K, Araki T, Ieda S, Ohtsuka M, Inagaki Y, Honda A, Kagawa T, Kamiya A. Abcb4-defect cholangitis mouse model with hydrophobic bile acid composition by in vivo liver-specific gene deletion. J Lipid Res 2024; 65:100616. [PMID: 39111549 PMCID: PMC11407928 DOI: 10.1016/j.jlr.2024.100616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 07/29/2024] [Accepted: 07/30/2024] [Indexed: 09/06/2024] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is a liver disease that occurs during childhood and requires liver transplantation. ABCB4 is localized along the canalicular membranes of hepatocytes, transports phosphatidylcholine into bile, and its mutation causes PFIC3. Abcb4 gene-deficient mice established as animal models of PFIC3 exhibit cholestasis-induced liver injury. However, their phenotypes are often milder than those of human PFIC3, partly because of the existence of large amounts of less toxic hydrophilic bile acids synthesized by the rodent-specific enzymes Cyp2c70 and Cyp2a12. Mice with double deletions of Cyp2c70/Cyp2a12 (CYPDKO mice) have a human-like hydrophobic bile acid composition. PFIC-related gene mutations were induced in CYPDKO mice to determine whether these triple-gene-deficient mice are a better model for PFIC. To establish a PFIC3 mouse model using CYPDKO mice, we induced abcb4 gene deletion in vivo using adeno-associated viruses expressing SaCas9 under the control of a liver-specific promoter and abcb4-target gRNAs. Compared to Abcb4-deficient wild-type mice, Abcb4-deficient CYPDKO mice showed more pronounced liver injury along with an elevation of inflammatory and fibrotic markers. The proliferation of intrahepatic bile ductal cells and hematopoietic cell infiltration were also observed. CYPDKO/abcb4-deficient mice show a predominance of taurine-conjugated chenodeoxycholic acid and lithocholic acid in the liver. In addition, phospholipid levels in the gallbladder bile were barely detectable. Mice with both human-like bile acid composition and Abcb4-defect exhibit severe cholestatic liver injury and are useful for studying human cholestatic diseases and developing new treatments.
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Affiliation(s)
- Kota Tsuruya
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Keiko Yokoyama
- Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Support Center of Medical Research and Education, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Yusuke Mishima
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Kinuyo Ida
- Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Takuma Araki
- Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Support Center of Medical Research and Education, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Satsuki Ieda
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Masato Ohtsuka
- Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Yutaka Inagaki
- Center for Matrix Biology and Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Akira Honda
- Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan; Department of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Tatehiro Kagawa
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
| | - Akihide Kamiya
- Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
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Li ZD, Li YC, Jing-Zhao, Wang JS, Xie XB. NR1H4 disease: rapidly progressing neonatal intrahepatic cholestasis and early death. Orphanet J Rare Dis 2024; 19:171. [PMID: 38641832 PMCID: PMC11027519 DOI: 10.1186/s13023-024-03166-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 03/30/2024] [Indexed: 04/21/2024] Open
Abstract
BACKGROUND Clinical studies on progressive familial intrahepatic cholestasis (PFIC) type 5 caused by mutations in NR1H4 are limited. METHODS New patients with biallelic NR1H4 variants from our center and all patients from literature were retrospectively analyzed. RESULTS Three new patients were identified to be carrying five new variants. Liver phenotypes of our patients manifests as low-γ-glutamyl transferase cholestasis, liver failure and related complications. One patient underwent liver transplantation (LT) and survived, and two other patients died without LT. Nine other patients were collected through literature review. Twelve out of 13 patients showed neonatal jaundice, with the median age of onset being 7 days after birth. Reported clinical manifestations included cholestasis (13/13, 100%), elevated AFP (11/11, 100%), coagulopathy (11/11, 100%), hypoglycemia (9/13, 69%), failure to thrive (8/13, 62%), splenomegaly (7/13, 54%), hyperammonemia (7/13, 54%), and hepatomegaly (6/13, 46%). Six of 13 patients received LT at a median age of 6.2 months, and only one patient died of acute infection at one year after LT. Other 7 patients had no LT and died with a median age of 5 months (range 1.2-8). There were 8 patients with homozygous genotype and 5 patients with compound heterozygous genotype. In total, 13 different variants were detected, and 5 out of 12 single or multiple nucleotides variants were located in exon 5. CONCLUSIONS We identified three newly-diagnosed patients and five novel mutations. NR1H4-related PFIC typically cause progressive disease and early death. LT may be the only lifesaving therapy leading to cure.
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Affiliation(s)
- Zhong-Die Li
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, No. 399 Wanyuan Road, Minhang District, 201102, Shanghai, China
| | - Yu-Chuan Li
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, No. 399 Wanyuan Road, Minhang District, 201102, Shanghai, China
| | - Jing-Zhao
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, No. 399 Wanyuan Road, Minhang District, 201102, Shanghai, China
| | - Jian-She Wang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, No. 399 Wanyuan Road, Minhang District, 201102, Shanghai, China
| | - Xin-Bao Xie
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, No. 399 Wanyuan Road, Minhang District, 201102, Shanghai, China.
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10
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Yao Z, Chen L, Hu M, Meng F, Chen M, Wang G. The discovery of a new potent FXR agonist based on natural product screening. Bioorg Chem 2024; 143:106979. [PMID: 37995646 DOI: 10.1016/j.bioorg.2023.106979] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 11/07/2023] [Accepted: 11/15/2023] [Indexed: 11/25/2023]
Abstract
FXR agonistic activity screening was conducted based on natural product resources containing 38 structurally diverse sesquiterpenoids isolated from Xylopia vielana. Among them, 34 undescribed sesquiterpenoids with 5 different skeleton types were first characterized by HRESIMS, NMR data, ECD calculations and X-ray crystallographic analysis. High-content screening for FXR agonistic activity of these compounds demonstrated that 13 compounds could activate FXR. Then molecular docking results suggested that hydrogen bonding and hydrophobic interactions might contribute to the main interaction of active compounds with FXR. The preliminary structure-activity relationships (SARs) of those isolates were also discussed. The most potent compound 27 significantly elevated the transcriptional activity of the FXR target gene BSEP promoter (EC50 = 14.26 μM) by a dual-luciferase reporter assay. Western blotting indicated that compound 27 activated the FXR-associated pathway, thereby upregulating SHP and BSEP expression, and downregulating CYP7A1 and NTCP expression. We further revealed that FXR was the target protein of compound 27 through diverse target validation methods, including CETSA, SIP, and DARTS under the intervention of temperature, organic reagents and protease. Pharmacological in vivo experiments showed that compound 27 effectively ameliorated α-naphthyl isothiocyanate (ANIT)-induced cholestasis in mice, as evidenced by the ameliorative histopathology of the liver and the decrease in biochemical markers: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), direct bilirubin (DBIL), and total bile acid (TBA). This work showed a practical strategy for the discovery of new FXR agonists from natural products and provided potential insights for sesquiterpenoids as FXR agonist lead compounds.
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Affiliation(s)
- Zongwen Yao
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Lin Chen
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Min Hu
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Fancheng Meng
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Min Chen
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
| | - Guowei Wang
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
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11
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Wu G, Wei X, Li D, Xiao G, Jia C, Zeng Z, Chen Z. Selection and evaluation of quality markers for the regulation of PXR-CYP3A4/FXR-LXRα by Exocarpium Citri Grandis for the treatment of hyperlipidaemia with dispelling blood stasis and removing phlegm. Biomed Pharmacother 2024; 170:116089. [PMID: 38157640 DOI: 10.1016/j.biopha.2023.116089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 12/19/2023] [Accepted: 12/26/2023] [Indexed: 01/03/2024] Open
Abstract
Hyperlipidaemia is described as "excessive phlegm" and "blood stasis" in the classic theory of traditional Chinese medicine. Exocarpium Citri Grandis has the effect of dispelling blood stasis and removing phlegm, which can better meet the treatment needs of this disease. However, there is still a lack of focus and depth in the study of the chemical composition of this medicine, and the correlation between the study of relevant medicinal substances and the efficacy of dispelling stasis and removing phlegm is insufficient. To address this issue, this study was carried out to validate the overall efficacy and identify and determine the chemical composition of Exocarpium Citri Grandis. The regulatory mechanism of the PXR-CYP3A4/FXR-LXRα pathway and its active ingredients were screened, and a pharmacokinetic study of active ingredients was performed. The obtained multidimensional data were statistically analysed and comprehensively evaluated. The quality marker of Exocarpium Citri Grandis in the treatment of hyperlipidaemia based on the PXR-CYP3A4/FXR-LXRα mechanism to exert the efficacy of dispelling blood stasis and removing phlegm was finally determined. Based on the above experiments, we identified 27 compounds from the ethanol extract of Exocarpium Citri Grandis. Among them, naringenin, meranzin hydrate, apigenin, caffeic acid phenethyl ester, anacardiin, hesperidin and naringin can significantly regulate all or part of the targets in the PXR-CYP3A4/FXR-LXRα pathway. It also has suitable content and pharmacokinetic characteristics in vivo. In conclusion, this study established quality markers to characterize the efficacy of Exocarpium Citri Grandis in dispelling blood stasis and removing phlegm, which provides a scientific basis for the targeted evaluation of the hypolipidaemic activity of this medicinal plant.
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Affiliation(s)
- Guangying Wu
- The Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd, Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd, Guangzhou 510095, China
| | - Xingqin Wei
- The Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd, Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd, Guangzhou 510095, China
| | - Dongmei Li
- The Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd, Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd, Guangzhou 510095, China
| | - Guanlin Xiao
- The Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd, Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd, Guangzhou 510095, China
| | - Canchao Jia
- The Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd, Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd, Guangzhou 510095, China
| | - Zhihao Zeng
- The Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd, Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd, Guangzhou 510095, China
| | - Zhao Chen
- The Fifth College of Clinic Medicine, Guangzhou University of Chinese Medicine, 60 Hengfu rd, Guangzhou 510095, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, 60 Hengfu rd, Guangzhou 510095, China.
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12
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Cifuentes-Silva E, Cabello-Verrugio C. Bile Acids as Signaling Molecules: Role of Ursodeoxycholic Acid in Cholestatic Liver Disease. Curr Protein Pept Sci 2024; 25:206-214. [PMID: 37594109 DOI: 10.2174/1389203724666230818092800] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/05/2023] [Accepted: 07/18/2023] [Indexed: 08/19/2023]
Abstract
Ursodeoxycholic acid (UDCA) is a natural substance physiologically produced in the liver. Initially used to dissolve gallstones, it is now successfully used in treating primary biliary cirrhosis and as adjuvant therapy for various hepatobiliary cholestatic diseases. However, the mechanisms underlying its beneficial effects still need to be clarified. Evidence suggests three mechanisms of action for UDCA that could benefit humans with cholestatic liver disease (CLD): protection of cholangiocytes against hydrophobic bile acid (BA) cytotoxicity, stimulation of hepatobiliary excretion, and protection of hepatocytes against BA-induced apoptosis. These mechanisms may act individually or together to potentiate them. At the molecular level, it has been observed that UDCA can generate modifications in the transcription and translation of proteins essential in the transport of BA, correcting the deficit in BA secretion in CLD, in addition to activating signaling pathways to translocate these transporters to the sites where they should fulfill their function. Inhibition of BA-induced hepatocyte apoptosis may play a role in CLD, characterized by BA retention in the hepatocyte. Thus, different mechanisms of action contribute to the improvement after UDCA administration in CLD. On the other hand, the effects of UDCA on tissues that possess receptors that may interact with BAs in pathological contexts, such as skeletal muscle, are still unclear. This work aims to describe the main molecular mechanisms by which UDCA acts in the human body, emphasizing the interaction in tissues other than the liver.
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Affiliation(s)
- Eduardo Cifuentes-Silva
- Laboratory of Muscle Pathology, Fragility, and Aging, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
| | - Claudio Cabello-Verrugio
- Laboratory of Muscle Pathology, Fragility, and Aging, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
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13
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Xiao L, Xu G, Chen S, He Y, Peng F, Yuan C. Kaempferol ameliorated alcoholic liver disease through inhibiting hepatic bile acid synthesis by targeting intestinal FXR-FGF15 signaling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 120:155055. [PMID: 37678053 DOI: 10.1016/j.phymed.2023.155055] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 08/16/2023] [Accepted: 08/29/2023] [Indexed: 09/09/2023]
Abstract
BACKGROUND Alcoholic liver disease (ALD) is characterized by the disturbance of bile acids homeostasis, which further deteriorates ALD. Bile acid metabolism and its related signal molecules have become new therapeutic targets for alcoholic liver disease. This study aimed to investigate the impact of kaempferol (KAE) on ALD and elucidate its underlying mechanisms. METHODS C57BL/6 N mice were utilized to establish Binge-on-Chronic alcohol exposure mice model. KAE was administered as an interventional drug to chronic alcohol-fed mice for four weeks to assess its effects on liver damage and bile acid metabolism. And Z-Guggulsterone (Z-Gu), a global FXR inhibitor, was used to investigate the impact of intestinal FXR-FGF15 signal in ALD mice. Additionally, intestinal epithelial cells were exposed to alcohol or specific bile acid to induce the damage of FXR activity in vitro. The dual luciferase activity assay was employed to ascertain the interplay between KAE and FXR activity. RESULTS The results indicated that KAE treatment exhibited a significant hepatoprotective effect against chronic alcohol-fed mice. Accompanied by the intestinal FXR activation, the administration of KAE suppressed hepatic bile acid synthesis and promoted intestinal bile acid excretion in chronic ALD mice. And the notable alterations in total bile acid levels and composition were observed in mice after chronic alcohol feeding, which were reversed by KAE supplementation. And more, the protective effects of KAE on ALD mice were deprived by the inhibition of intestinal FXR activation. In vitro experiments demonstrated that KAE effectively activated FXR-FGF15 signaling, mitigated the damage to FXR activity in intestinal epithelial cells caused by alcohol or specific bile acids. Additionally, luciferase activity assays revealed that KAE directly promoted FXR expression, thereby enhancing FXR activity. CONCLUSION KAE treatment inhibited hepatic bile acids synthesis, maintained bile acids homeostasis in ALD mice by directly activating intestinal FXR-FGF15 signaling, which effectively alleviated liver injury induced by chronic alcohol consumption.
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Affiliation(s)
- Li Xiao
- College of Basic Medical Science, China Three Gorges University, Yichang, China; Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, College of Medicine and Health Sciences, China Three Gorges University, Yichang, China
| | - Guangfu Xu
- College of Basic Medical Science, China Three Gorges University, Yichang, China
| | - Silong Chen
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, College of Medicine and Health Sciences, China Three Gorges University, Yichang, China
| | - Yumin He
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, College of Medicine and Health Sciences, China Three Gorges University, Yichang, China
| | - Fan Peng
- College of Basic Medical Science, China Three Gorges University, Yichang, China
| | - Chengfu Yuan
- College of Basic Medical Science, China Three Gorges University, Yichang, China; Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, College of Medicine and Health Sciences, China Three Gorges University, Yichang, China.
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14
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Liu Y, Huang K, Zhang Y, Cao H, Guan X. Dietary polyphenols maintain homeostasis via regulating bile acid metabolism: a review of possible mechanisms. Food Funct 2023; 14:9486-9505. [PMID: 37815149 DOI: 10.1039/d3fo02471g] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/11/2023]
Abstract
The synthesis and metabolism of bile acids (BAs) have been implicated in various metabolic diseases, including obesity and diabetes. Dietary polyphenols, as natural antioxidants, play a vital role in synthesizing and metabolizing bile acids. This paper reviews the mechanism of dietary polyphenols involved in bile acid (BA) synthesis and metabolism. The impact of different gut microorganisms on BA profiles is discussed in detail. The regulation of BA metabolism by dietary polyphenols can be divided into two modes: (1) dietary polyphenols directly activate/inhibit farnesol X receptor (FXR) and Takeda G protein-coupled receptor (TGR5); (2) dietary polyphenols regulate BA synthesis and metabolism through changes in intestinal microorganisms. Research on direct activation/inhibition of FXR and TGR5 by polyphenols should be ramped up. In addition, the effect of dietary polyphenols on intestinal microorganisms has been paid more and more attention and has become a target that cannot be ignored.
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Affiliation(s)
- Yongyong Liu
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, PR China.
| | - Kai Huang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, PR China.
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai, PR China
| | - Yu Zhang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, PR China.
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai, PR China
| | - Hongwei Cao
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, PR China.
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai, PR China
| | - Xiao Guan
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, PR China.
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai, PR China
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15
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Chen J, Zhang S. The Role of Inflammation in Cholestatic Liver Injury. J Inflamm Res 2023; 16:4527-4540. [PMID: 37854312 PMCID: PMC10581020 DOI: 10.2147/jir.s430730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 10/06/2023] [Indexed: 10/20/2023] Open
Abstract
Cholestasis is a common clinical event in which bile formation and excretion are blocked, leading to retention of bile acids or bile salts; whether it occurs intra- or extrahepatically, primary or secondary, its pathogenesis is still unclear and is influenced by a combination of factors. In a variety of inflammatory and immune cells such as neutrophils, macrophages (intrahepatic macrophages are also known as Kupffer cells), mast cells, NK cells, and even T cells in humoral immunity and B cells in cellular immunity, inflammation can be a "second strike" against cholestatic liver injury. These cells, stimulated by a variety of factors such as bile acids, inflammatory chemokines, and complement, can be activated and accumulate in the cholestatic liver, and with the involvement of inflammatory mediators and modulation by cytokines, can lead to destruction of hepatocytes and bile duct epithelial cells and exacerbate (and occasionally retard) the progression of cholestatic liver disease. In this paper, we summarized the new research advances proposed so far regarding the relationship between inflammation and cholestasis, aiming to provide reference for researchers and clinicians in the field of cholestatic liver injury research.
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Affiliation(s)
- Jie Chen
- Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, Department of Infectious Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Shujun Zhang
- Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, Department of Infectious Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
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16
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Fu Y, Lyu J, Wang S. The role of intestinal microbes on intestinal barrier function and host immunity from a metabolite perspective. Front Immunol 2023; 14:1277102. [PMID: 37876938 PMCID: PMC10591221 DOI: 10.3389/fimmu.2023.1277102] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 09/21/2023] [Indexed: 10/26/2023] Open
Abstract
The gut is colonized by many commensal microorganisms, and the diversity and metabolic patterns of microorganisms profoundly influence the intestinal health. These microbial imbalances can lead to disorders such as inflammatory bowel disease (IBD). Microorganisms produce byproducts that act as signaling molecules, triggering the immune system in the gut mucosa and controlling inflammation. For example, metabolites like short-chain fatty acids (SCFA) and secondary bile acids can release inflammatory-mediated signals by binding to specific receptors. These metabolites indirectly affect host health and intestinal immunity by interacting with the intestinal epithelial and mucosal immune cells. Moreover, Tryptophan-derived metabolites also play a role in governing the immune response by binding to aromatic hydrocarbon receptors (AHR) located on the intestinal mucosa, enhancing the intestinal epithelial barrier. Dietary-derived indoles, which are synthetic precursors of AHR ligands, work together with SCFA and secondary bile acids to reduce stress on the intestinal epithelium and regulate inflammation. This review highlights the interaction between gut microbial metabolites and the intestinal immune system, as well as the crosstalk of dietary fiber intake in improving the host microbial metabolism and its beneficial effects on the organism.
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Affiliation(s)
- Yifeng Fu
- Department of Cardiology, The Affiliated Wenling Hospital of Wenzhou Medical University (The First People’s Hospital of Wenling), Wenling, Zhejiang, China
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan, China
| | - Jin Lyu
- Department of Pathology, the First People’s Hospital of Foshan, Foshan, Guangdong, China
| | - Shuangshuang Wang
- Department of Cardiology, The Affiliated Wenling Hospital of Wenzhou Medical University (The First People’s Hospital of Wenling), Wenling, Zhejiang, China
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17
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Kasztelan-Szczerbinska B, Rycyk-Bojarzynska A, Szczerbinska A, Cichoz-Lach H. Selected Aspects of the Intricate Background of Immune-Related Cholangiopathies-A Critical Overview. Nutrients 2023; 15:760. [PMID: 36771465 PMCID: PMC9921714 DOI: 10.3390/nu15030760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/28/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are rare immune-related cholangiopathies with still poorly explained pathogenesis. Although triggers of chronic inflammation with subsequent fibrosis that affect cholangiocytes leading to obliteration of bile ducts and conversion to liver cirrhosis are unclear, both disorders are regarded to be multifactorial. Different factors can contribute to the development of hepatocellular injury in the course of progressive cholestasis, including (1) body accumulation of bile acids and their toxicity, (2) decreased food intake and nutrient absorption, (3) gut microbiota transformation, and (4) reorganized host metabolism. Growing evidence suggests that intestinal microbiome composition not only can be altered by liver dysfunction, but in turn, it actively impacts hepatic conditions. In this review, we highlight the role of key factors such as the gut-liver axis, intestinal barrier integrity, bile acid synthesis and circulation, and microbiome composition, which seem to be strongly related to PBC and PSC outcome. Emerging treatments and future therapeutic strategies are also presented.
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Affiliation(s)
- Beata Kasztelan-Szczerbinska
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
| | - Anna Rycyk-Bojarzynska
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
| | | | - Halina Cichoz-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, 8 Jaczewski Street, 20-954 Lublin, Poland
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18
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Dai Y, Jia Z, Fang C, Zhu M, Yan X, Zhang Y, Wu H, Feng M, Liu L, Huang B, Li Y, Liu J, Xiao H. Polygoni Multiflori Radix interferes with bile acid metabolism homeostasis by inhibiting Fxr transcription, leading to cholestasis. Front Pharmacol 2023; 14:1099935. [PMID: 36950015 PMCID: PMC10025474 DOI: 10.3389/fphar.2023.1099935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 02/20/2023] [Indexed: 03/08/2023] Open
Abstract
Objective: To explore the possible mechanisms of cholestasis induced by Polygoni Multiflori Radix (PM). Methods: Low and high doses of water extract of PM were given to mice by gavage for 8 weeks. The serum biochemical indexes of aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamyltransferase (GGT) alkaline phosphatase (ALP) and so on were detected in the second, fourth, sixth, and eighth weeks after administration. At the end of the eighth week of administration, the bile acid metabolic profiles of liver and bile were screened by high-performance liquid chromatography tandem triple quadrupole mass spectrometry (HPLC-QQQ-MS/MS). Liver pathological changes were observed by hematoxylin and eosin staining. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the mRNA transcription of the target genes and Western blotting (WB) was used to the detect target protein expression. Results: Biochemical tests results showed the values of ALP and GGT were two and three times greater than the normal values respectively, and the value of R was less than 2. Histopathology also showed that PM caused lymphocyte infiltration, a small amount of hepatocyte necrosis and nuclear fragmentation in mouse liver. The proliferation of bile duct epithelial cells was observed in the high group. These results indicated that PM may lead to cholestatic liver injury. HPLC-QQQ-MS/MS analysis with the multivariate statistical analysis revealed significant alterations of individual bile acids in liver and gallbladder as compared to those of the control group. RT-qPCR showed that the transcription of Fxr, Shp, Bsep, Bacs, Mdr2, and Ugt1a1 were downregulated and that of Cyp7a1, Mrp3, and Cyp3a11 was significantly upregulated in the treatment group. WB demonstrated that PM also markedly downregulated the protein expression of FXR, BSEP, and MDR2, and upregulated CYP7A1. Conclusion: PM inhibited the expression of FXR, which reduced the expression of MDR2 and BSEP, leading to the obstruction of bile acids outflow, and increased the expression of CYP7A1, resulting in an increase of intrahepatic bile acid synthesis, which can lead to cholestasis.
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Affiliation(s)
- Yihang Dai
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhixin Jia
- Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China
- Beijing Academy of Traditional Chinese Medicine, Beijing, China
| | - Cong Fang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Meixia Zhu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoning Yan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yinhuan Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Hao Wu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Menghan Feng
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Lirong Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Beibei Huang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yueting Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jie Liu
- Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China
- Beijing Academy of Traditional Chinese Medicine, Beijing, China
| | - Hongbin Xiao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China
- Beijing Academy of Traditional Chinese Medicine, Beijing, China
- *Correspondence: Hongbin Xiao,
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19
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Mechanism and Active Components of Qingre Lidan Tablets Alleviate Intrahepatic Cholestasis by Activating the Farnesoid X Receptor. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1589388. [PMID: 36506808 PMCID: PMC9729052 DOI: 10.1155/2022/1589388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 10/18/2022] [Accepted: 11/15/2022] [Indexed: 12/05/2022]
Abstract
Background Qingre Lidan tablets (QLTs) are a compound preparation of Chinese medicine that have long been used clinically to treat poor bile circulation caused by the inflammation and obstruction of the gallbladder and bile duct and to relieve jaundice and other symptoms. However, its material basis and mechanism are still unclear. The purpose of this study was to investigate the mechanism and active components of QLTs for treating intrahepatic cholestasis (IHC) in rat models. Methods In vivo experiments verified the effect of QLTs on alpha-naphthyl isothiocyanate (ANIT)-induced IHC models in rats. The mRNA and protein expression levels of farnesoid X receptor (FXR), bile salt export pump (BSEP), and multidrug-associated protein 2 (MRP2) in the rat liver were detected. UPLC/Q-TOF-MS was used to separate and identify the monomers in QLTs, and a dual-luciferase reporter assay was used to select effective the monomers that stimulate FXR. Among the selected monomers, baicalein was used as a representative to verify the effect on rat IHC models. Results QLTs and baicalein significantly reduced the serum biochemical indicators reflecting the changes in liver function among IHC rats and remitted the ANIT-induced liver histopathological changes. The expression levels of FXR, BSEP, and MRP2 in the liver were significantly increased after QLT treatment in a dose-dependent manner. Moreover, six types of active components that activate FXR were selected in QLTs, namely baicalein, wogonin, baicalein II, emodin, dibutyl phthalate, and diisooctyl phthalate. Conclusions QLTs and the active component, baicalein, can alleviate IHC in model rats.
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Abstract
Bile acids wear many hats, including those of an emulsifier to facilitate nutrient absorption, a cholesterol metabolite, and a signaling molecule in various tissues modulating itching to metabolism and cellular functions. Bile acids are synthesized in the liver but exhibit wide-ranging effects indicating their ability to mediate organ-organ crosstalk. So, how does a steroid metabolite orchestrate such diverse functions? Despite the inherent chemical similarity, the side chain decorations alter the chemistry and biology of the different bile acid species and their preferences to bind downstream receptors distinctly. Identification of new modifications in bile acids is burgeoning, and some of it is associated with the microbiota within the intestine. Here, we provide a brief overview of the history and the various receptors that mediate bile acid signaling in addition to its crosstalk with the gut microbiota.
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Affiliation(s)
| | | | - Sayeepriyadarshini Anakk
- Correspondence: Sayeepriyadarshini Anakk, PhD, Department of Molecular & Integrative Physiology, University of Illinois at Urbana-Champaign, 506 S Mathews Ave, 453 Medical Sciences Bldg, Urbana, IL 61801, USA.
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21
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Obeticholic Acid for Primary Biliary Cholangitis. Biomedicines 2022; 10:biomedicines10102464. [PMID: 36289726 PMCID: PMC9599277 DOI: 10.3390/biomedicines10102464] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 09/09/2022] [Accepted: 09/28/2022] [Indexed: 11/25/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a rare autoimmune cholestatic liver disease that may progress to fibrosis and/or cirrhosis. Treatment options are currently limited. The first-line therapy for this disease is the drug ursodeoxycholic acid (UDCA), which has been proven to normalize serum markers of liver dysfunction, halt histologic disease progression, and lead to a prolongation of transplant-free survival. However, 30–40% of patients unfortunately do not respond to this first-line therapy. Obeticholic acid (OCA) is the only registered agent for second-line treatment in UDCA-non responders. In this review, we focus on the pharmacological features of OCA, describing its mechanism of action of and its tolerability and efficacy in PBC patients. We also highlight current perspectives on future therapies for this condition.
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22
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Liu D, Ji Y, Cheng Q, Zhu Y, Zhang H, Guo Y, Cao X, Wang H. Dietary astaxanthin-rich extract ameliorates atherosclerosis/retinopathy and restructures gut microbiome in apolipoprotein E-deficient mice fed on a high-fat diet. Food Funct 2022; 13:10461-10475. [PMID: 36134474 DOI: 10.1039/d2fo02102a] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Scope: Atherosclerosis (AS) is the leading cause of ischemic disease. However, the anti-AS effects of astaxanthin and its potential mechanisms remain unclear. This study is aimed to investigate the function of astaxanthin-rich extract (ASTE) on AS and gut microbiota as well as the difference from atorvastatin (ATO) in apolipoprotein E-deficient (ApoE-/-) mice. Methods and results: Wild type (WT) and ApoE-/- mice were divided into seven groups: the low-fat diet (LFD) and high-fat diet (HFD) groups (in both types) as well as three ApoE-/- groups based on HFD added with two doses of ASTE and one dose of ATO, respectively. After 30 weeks of intervention, results showed that ASTE significantly inhibited body weight increase, lipids accumulation in serum/liver, and AS-lesions in the aorta. Furthermore, fundus fluorescein angiography and retinal CD31 immunohistochemical staining showed that ASTE could alleviate the occurrence of AS-retinopathy. H&E staining showed that ASTE could protect the colon's mucosal epithelium from damage. The gas chromatographic and gene expression analyses showed that ASTE promoted the excretion of fecal acidic and neutral sterols from cholesterol by increasing LXRα, CYP7A1, and ABCG5/8 and decreasing FXR, NPC1L1, ACAT2, and MTTP expressions. Remarkably, the ASTE administration maintained the gut barrier by enhancing gene expression of JAM-A, Occludin, and mucin2 in the colon and reshaped gut microbiota with the feature of blooming Akkermansia. Conclusion: Our results suggested that ASTE could prevent AS in both macrovascular and/or microvascular as well as used as novel prebiotics by supporting the bile acid excretion and growth of Akkermansia.
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Affiliation(s)
- Dong Liu
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology, No. 29, 13th Avenue, Economic and Technological Development Area (TEDA), Tianjin 300457, China. .,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Yanglin Ji
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology, No. 29, 13th Avenue, Economic and Technological Development Area (TEDA), Tianjin 300457, China.
| | - Qian Cheng
- Angel Nutritech Company Limited, Yichang 443000, China
| | - Yamin Zhu
- Angel Nutritech Company Limited, Yichang 443000, China
| | - Haibo Zhang
- Angel Nutritech Company Limited, Yichang 443000, China
| | - Yatu Guo
- Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Hospital, Tianjin Eye Institute, Tianjin 300384, China
| | - Xiupeng Cao
- The First People's Hospital of Neijiang, Neijiang 641099, China
| | - Hao Wang
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology, No. 29, 13th Avenue, Economic and Technological Development Area (TEDA), Tianjin 300457, China.
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Metabolomic-based investigation of Yinlan alleviating hyperlipidemia by inhibiting blood stasis and phlegm turbidity through the PXR-CYP3A4-ABCB1-FXR pathway. ARAB J CHEM 2022. [DOI: 10.1016/j.arabjc.2022.104272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Cai J, Rimal B, Jiang C, Chiang JYL, Patterson AD. Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther 2022; 237:108238. [PMID: 35792223 DOI: 10.1016/j.pharmthera.2022.108238] [Citation(s) in RCA: 190] [Impact Index Per Article: 63.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/13/2022] [Accepted: 06/27/2022] [Indexed: 11/24/2022]
Abstract
The diversity, composition, and function of the bacterial community inhabiting the human gastrointestinal tract contributes to host health through its role in producing energy or signaling molecules that regulate metabolic and immunologic functions. Bile acids are potent metabolic and immune signaling molecules synthesized from cholesterol in the liver and then transported to the intestine where they can undergo metabolism by gut bacteria. The combination of host- and microbiota-derived enzymatic activities contribute to the composition of the bile acid pool and thus there can be great diversity in bile acid composition that depends in part on the differences in the gut bacteria species. Bile acids can profoundly impact host metabolic and immunological functions by activating different bile acid receptors to regulate signaling pathways that control a broad range of complex symbiotic metabolic networks, including glucose, lipid, steroid and xenobiotic metabolism, and modulation of energy homeostasis. Disruption of bile acid signaling due to perturbation of the gut microbiota or dysregulation of the gut microbiota-host interaction is associated with the pathogenesis and progression of metabolic disorders. The metabolic and immunological roles of bile acids in human health have led to novel therapeutic approaches to manipulate the bile acid pool size, composition, and function by targeting one or multiple components of the microbiota-bile acid-bile acid receptor axis.
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Affiliation(s)
- Jingwei Cai
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Bipin Rimal
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, PR China
| | - John Y L Chiang
- Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
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Overi D, Carpino G, Cristoferi L, Onori P, Kennedy L, Francis H, Zucchini N, Rigamonti C, Viganò M, Floreani A, D’Amato D, Gerussi A, Venere R, Alpini G, Glaser S, Alvaro D, Invernizzi P, Gaudio E, Cardinale V, Carbone M. Role of ductular reaction and ductular-canalicular junctions in identifying severe primary biliary cholangitis. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2022; 4:100556. [PMID: 36267871 PMCID: PMC9576897 DOI: 10.1016/j.jhepr.2022.100556] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 07/21/2022] [Accepted: 08/03/2022] [Indexed: 11/29/2022]
Abstract
Background & Aims Primary biliary cholangitis (PBC) is a chronic cholangiopathy characterised by immuno-mediated injury of interlobular bile ducts leading to intrahepatic cholestasis and progressive liver fibrosis. PBC histology is characterised by portal inflammation, progressive fibrosis, ductopenia, and the appearance of the so-called ductular reaction. The aim of the present study was to investigate the pathogenetic relevance of ductular reaction in PBC. Methods Liver biopsies were collected from naïve people with PBC (N = 87). Clinical-serological parameters were obtained at diagnosis and after 1 year of ursodeoxycholic acid (UDCA) treatment. Histological staging was performed on all slides according to multiple scoring systems and criteria for PBC. Liver samples were obtained from Mdr2 -/- mice treated with or without UDCA. Samples were processed for histology, immunohistochemistry, and immunofluorescence. Results Ductular reaction in people with PBC correlated with the disease stage and liver fibrosis, but not with disease activity; an extensive ductular reaction correlated with serum alkaline phosphatase levels at diagnosis, response to UDCA, and individuals' estimated survival, independently from other histological parameters, including disease stage. In people with PBC, reactive ductules were associated with the establishment of junctions with bile canaliculi and with fibrogenetic cell activation. Consistently, in a mouse model of intrahepatic cholestasis, UDCA treatment was effective in reducing ductular reaction and fibrosis and increasing ductular-canalicular junctions. Conclusions Extensive ductular reaction outlines a severe histologic phenotype in PBC and is associated with an inadequate therapy response and a worse estimated prognosis. Lay summary In people affected by primary biliary cholangitis (PBC), the histological appearance of extensive ductular reaction identifies individuals at risk of progressive fibrosis. Ductular reaction at diagnosis correlates with the lack of response to first-line therapy with ursodeoxycholic acid and serves to restore ductular-canalicular junctions in people with PBC. Assessing ductular reaction extension at diagnosis may add valuable information for clinicians.
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Key Words
- AE2, anion exchanger 2
- ALP, alkaline phosphatase
- ALPt0, ALP at diagnosis
- ALPt12, ALP at 12 months after UDCA therapy
- ALT, alanine aminotransferase
- ALTt0, ALT at diagnosis
- AMA, antimitochondrial antibody
- ANA, antinuclear antibody
- AST, aspartate aminotransferase
- ASTt0, AST at diagnosis
- BAC, bile acid control
- BIL, bilirubin
- BILt0, BIL at diagnosis
- CA, cholangitis activity
- CK19, cytokeratin 19
- CK7, cytokeratin 7
- Cholangiopathy
- Cholestasis
- DCJ, ductular–canalicular junction
- DCJ/d, DCJ per ductule
- DCJ/pt, DCJ per portal tract
- DR, ductular reaction
- EpCAM, epithelial cell adhesion molecule
- GGT, gamma-glutamyl transferase
- HA, hepatitis activity
- HSC, hepatic stellate cell
- Histology
- IH, intermediate hepatocyte
- Liver biopsy
- MF, myofibroblast
- Muc-1, mucin 1
- PBC, primary biliary cholangitis
- PCNA, proliferating cell nuclear antigen
- RT-qPCR, real-time quantitative PCR
- Regeneration
- SCTR, secretin receptor
- SQ, semiquantitative
- UDCA, ursodeoxycholic acid
- ULN, upper limit of normal
- URS, UDCA response score
- Ursodeoxycholic acid
- WT, wild type
- αSMA, α-smooth muscle actin
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Affiliation(s)
- Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome ‘Foro Italico’, Rome, Italy,Corresponding author. Address: Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome ‘Foro Italico’, Rome, Italy. Piazza Lauro De Bosis 6, 00135-Rome, Italy. Tel./Fax: +39-06-36733-202..
| | - Laura Cristoferi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Lindsey Kennedy
- Hepatology and Gastroenterology, Medicine, Indiana University School of Medicine, Indianapolis, IN, USA,Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
| | - Heather Francis
- Hepatology and Gastroenterology, Medicine, Indiana University School of Medicine, Indianapolis, IN, USA,Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
| | - Nicola Zucchini
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Cristina Rigamonti
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale ‘A. Avogadro’, Novara, Italy
| | - Mauro Viganò
- Division of Hepatology, Ospedale San Giuseppe, University of Milan, Milan, Italy
| | - Annarosa Floreani
- Studiosa Senior, University of Padua, Padua, Italy,Scientific Consultant, IRCCS Negrar, Verona, Italy
| | - Daphne D’Amato
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Alessio Gerussi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Rosanna Venere
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Gianfranco Alpini
- Hepatology and Gastroenterology, Medicine, Indiana University School of Medicine, Indianapolis, IN, USA,Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, USA
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Marco Carbone
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
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Liu J, Liu J, Meng C, Huang C, Liu F, Xia C. Oleanolic acid alleviates ANIT-induced cholestatic liver injury by activating Fxr and Nrf2 pathways to ameliorate disordered bile acids homeostasis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 102:154173. [PMID: 35605478 DOI: 10.1016/j.phymed.2022.154173] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/24/2022] [Accepted: 05/12/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Cholestasis is a clinical syndrome with high incidence and few effective treatments. Oleanolic acid (OA) is a triterpenoid compound with anti-cholestatic effects. Studies using bile duct ligation or lithocholic acid modeling have shown that the alleviating effect of OA on cholerosis is related to the regulation of nuclear factor erythroid 2 related factor (Nrf2) or farnesoid X receptor (Fxr). PURPOSE This study aims to investigate the underlying mechanism of OA against alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury based on Nrf2 and Fxr dual signaling pathways. METHODS The ANIT-induced rats model was used with or without OA treatment. Serum biochemical indexes, liver histopathological changes and glutathione level were examined. Bile acids (BAs) targeted metabolomics based on UHPLC-MS/MS were performed. siRNA, RT-qPCR and western blot analysis were used to prove the role of Fxr and Nrf2 pathway in OA's anti-cholestatic liver injury in vivo and in vitro. RESULTS OA significantly alleviated ANIT-induced liver injury in rats, reduced primary bile acids, accelerated metabolism of BAs and reduced the intrahepatic accumulation of BAs. The expressions of bile salt export pump (Bsep), Na+-taurocholic cotransport polypeptide (Ntcp), UDP-glucuronyl transferase 1a1 (Ugt1a1) and Fxr in rat liver were markedly up-regulated, the activation of Nrf2 was promoted, and the expression of cholesterol 7α-hydroxylase (Cyp7a1) was decreased after OA treatment. Moreover, Fxr or Nrf2 silencing attenuated the regulation of OA on BAs homeostasis related transporters and enzymes in rat primary hepatocytes. CONCLUSION OA may regulate BAs-related transporters and metabolic enzymes by activating Fxr and Nrf2 pathways, thus alleviating the cholestatic liver injury induced by ANIT.
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Affiliation(s)
- Jianming Liu
- Institute of Clinical Pharmacology, School of Pharmacy, Nanchang University, Nanchang 330006, PR China
| | - Jiawei Liu
- Institute of Clinical Pharmacology, School of Pharmacy, Nanchang University, Nanchang 330006, PR China
| | - Chao Meng
- Institute of Clinical Pharmacology, School of Pharmacy, Nanchang University, Nanchang 330006, PR China
| | - Chao Huang
- Institute of Clinical Pharmacology, School of Pharmacy, Nanchang University, Nanchang 330006, PR China
| | - Fanglan Liu
- Institute of Clinical Pharmacology, School of Pharmacy, Nanchang University, Nanchang 330006, PR China
| | - Chunhua Xia
- Institute of Clinical Pharmacology, School of Pharmacy, Nanchang University, Nanchang 330006, PR China.
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Ye X, Zhang T, Han H. PPARα: A potential therapeutic target of cholestasis. Front Pharmacol 2022; 13:916866. [PMID: 35924060 PMCID: PMC9342652 DOI: 10.3389/fphar.2022.916866] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 06/29/2022] [Indexed: 12/12/2022] Open
Abstract
The accumulation of bile acids in the liver leads to the development of cholestasis and hepatocyte injury. Nuclear receptors control the synthesis and transport of bile acids in the liver. Among them, the farnesoid X receptor (FXR) is the most common receptor studied in treating cholestasis. The activation of this receptor can reduce the amount of bile acid synthesis and decrease the bile acid content in the liver, alleviating cholestasis. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) have a FXR excitatory effect, but the unresponsiveness of some patients and the side effect of pruritus seriously affect the results of UDCA or OCA treatment. The activator of peroxisome proliferator-activated receptor alpha (PPARα) has emerged as a new target for controlling the synthesis and transport of bile acids during cholestasis. Moreover, the anti-inflammatory effect of PPARα can effectively reduce cholestatic liver injury, thereby improving patients’ physiological status. Here, we will focus on the function of PPARα and its involvement in the regulation of bile acid transport and metabolism. In addition, the anti-inflammatory effects of PPARα will be discussed in some detail. Finally, we will discuss the application of PPARα agonists for cholestatic liver disorders.
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Affiliation(s)
- Xiaoyin Ye
- School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tong Zhang
- School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Tong Zhang, ; Han Han,
| | - Han Han
- Experiment Center for Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Tong Zhang, ; Han Han,
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Wang H, He S, Sun Z, Wang R, Zou X, Lu F. Targeted Profiling of Rodent Unconjugated Bile Acids by GC-MS to Reveal the Influence of High-Fat Diet. Biomed Chromatogr 2022; 36:e5428. [PMID: 35708903 DOI: 10.1002/bmc.5428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/27/2022] [Accepted: 06/14/2022] [Indexed: 11/10/2022]
Abstract
Unconjugated bile acids (BAs) have gained more attention than conjugated BAs in the association studies among diet, gut microbiota and diseases. Gas chromatography-mass spectrometry (GC-MS) is probably a good choice for specialized analysis of unconjugated BAs due to high separation capacity and identification convenience. However, few reports have focused on the rodent unconjugated BAs by GC-MS, and the main library for identification has not included rodent-specific BAs. We developed a GC-MS method for targeted profiling of eight main unconjugated BAs in rodent models, which showed excellent performance on sensitivity, reproducibility and accuracy. Quantitative reproducibility in terms of relative standard deviation (RSD) was in the range of 2.05%-2.91%, with detection limits of 3-55 ng/mL, quantitation limits of 9-182 ng/mL and the recovery rate of 72%-115%. All the calibration curves displayed good linearity with correlation coefficient values (R2 ) more than 0.99. Using the established method, the influence of high-fat diet on the metabolism of unconjugated BAs were revealed. Significant increasing of fecal unconjugated BAs induced by high-fat diet, would be a potential risk to gut inflammation and cancer. The study provides a convenient and targeted GC-MS method for specialized profiling of rodent unconjugated BAs in physiological and pathological studies.
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Affiliation(s)
- Hongbin Wang
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, The College of Biotechnology, Tianjin University of Science and Technology, Tianjin, P. R. China
| | - Shi He
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, The College of Biotechnology, Tianjin University of Science and Technology, Tianjin, P. R. China
| | - Zepeng Sun
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, The College of Biotechnology, Tianjin University of Science and Technology, Tianjin, P. R. China
| | - Ruijia Wang
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, The College of Biotechnology, Tianjin University of Science and Technology, Tianjin, P. R. China
| | - Xiaotong Zou
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, The College of Biotechnology, Tianjin University of Science and Technology, Tianjin, P. R. China
| | - Fuping Lu
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, The College of Biotechnology, Tianjin University of Science and Technology, Tianjin, P. R. China
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Yan M, Hou L, Cai Y, Wang H, Ma Y, Geng Q, Jiang W, Tang W. Effects of Intestinal FXR-Related Molecules on Intestinal Mucosal Barriers in Biliary Tract Obstruction. Front Pharmacol 2022; 13:906452. [PMID: 35770078 PMCID: PMC9234329 DOI: 10.3389/fphar.2022.906452] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/18/2022] [Indexed: 11/24/2022] Open
Abstract
Background: The farnesoid X receptor (FXR) is a key factor regulating hepatic bile acid synthesis and enterohepatic circulation. Repression of bile acid synthesis by the FXR is a potential strategy for treating cholestatic liver disease. However, the role of intestinal FXR on the intestinal barrier and intestinal microbiota needs further investigation. Materials: Intestinal tissues were collected from patients with biliary atresia or without hepatobiliary disease. Then, intestinal mRNA levels of FXR-related molecules were determined. To investigate the effect of FXR activation, bile-duct-ligation rats were treated with obeticholic acid [OCA (5 mg/kg/day)] or vehicle (0.5% methyl cellulose) per oral gavage for 14 days. The mRNA levels of intestinal FXR, SHP, TNF-α, FGF15 and bile acid transporter levels were determined. In addition, the intestinal permeability, morphologic changes, and composition of the intestinal microbiota were evaluated. Gut Microbiome was determined by 16S rDNA MiSeq sequencing, and functional profiling of microbial communities was predicted with BugBase and PICRUSt2. Finally, the role of OCA in injured intestinal epithelial cell apoptosis and proliferation was examined by pretreatment with lipopolysaccharide (LPS) in Caco-2 cells. Results: The downstream of the FXR in ileum tissues was inhibited in biliary obstruction. Activation of the FXR signaling pathway by OCA significantly reduced liver fibrosis and intestinal inflammation, improved intestinal microbiota, and protected intestinal mucosa in BDL rats. OCA also altered the functional capacities of ileum microbiota in BDL rats. Significant differences existed between the controls and BDL rats, which were attenuated by OCA in the alpha diversity analysis. Principal coordinates analysis showed that microbial communities in BDL rats clustered separately from controls, and OCA treatment attenuated the distinction. Bugbase and PICRUSt2 analysis showed that OCA changed the composition and structure of the intestinal microbiota and improved the metabolic function of the intestinal microbiota by increasing the relative abundance of beneficial bacteria and reducing the relative abundance of harmful bacteria. Moreover, OCA reduced the apoptosis induced by LPS in Caco-2 cells. Conclusion: The FXR agonist, OCA, activates the intestinal FXR signaling pathway and improves the composition and structure of the intestinal microbiota and intestinal barrier in BDL rats.
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Affiliation(s)
- Meng Yan
- Department of Pediatric Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Department of Pediatrics, Huai’an Maternal And Child Health Care center, Huai’an, China
| | - Li Hou
- Department of Pediatric Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Yaoyao Cai
- Department of Pediatric Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Hanfei Wang
- Department of Pediatric Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Yujun Ma
- Department of Pediatric Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Qiming Geng
- Department of Pediatric Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Weiwei Jiang
- Department of Pediatric Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Weiwei Jiang, ; Weibing Tang,
| | - Weibing Tang
- Department of Pediatric Surgery, Children’s Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Weiwei Jiang, ; Weibing Tang,
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Lai H, Liu X, Xin S, Zheng J, Liu H, Ouyang Y, Yang H, Zeng Y, Zou Y, Zeng X. Identification of two novel pathogenic variants of the NR1H4 gene in intrahepatic cholestasis of pregnancy patients. BMC Med Genomics 2022; 15:90. [PMID: 35436901 PMCID: PMC9017038 DOI: 10.1186/s12920-022-01240-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 04/12/2022] [Indexed: 12/18/2022] Open
Abstract
Background Intrahepatic cholestasis of pregnancy (ICP) can cause adverse pregnancy outcomes, such as spontaneous preterm delivery and stillbirth. It is a complex disease influenced by multiple factors, including genetics and the environment. Previous studies have reported that functioning nuclear receptor subfamily 1 group H member 4 (NR1H4) plays an essential role in bile acid (BA) homeostasis. However, some novel variants and their pathogenesis have not been fully elucidated. Therefore, this research aimed to investigate the genetic characteristics of the NR1H4 gene in ICP.
Methods In this study, we sequenced the entire coding region of NR1H4 in 197 pregnant women with ICP disease. SIFT and PolyPhen2 were used to predict protein changes. Protein structure modelling and comparisons between NR1H4 reference and modified protein structures were performed by SWISS-MODEL and Chimera 1.14rc, respectively. T-tests were used to analyse the potential significant differences between NR1H4 mutations and wild types for 29 clinical features. Fisher’s test was conducted to test the significance of differences in mutation frequencies between ICP and the three databases. Results We identified four mutations: two novel missense mutations, p.S145F and p.M185L; rs180957965 (A230S); and rs147030757 (N275N). The two novel missense mutations were absent in 1029 controls and three databases, including the 1000 Genomes Project (1000G_ALL), Exome Aggregation Consortium (ExAC) and ChinaMAP. Two web-available tools, SIFT and PolyPhen2, predicted that these mutations are harmful to the function of the protein. Moreover, compared to the wild-type protein structure, the NR1H4 p.S145F and p.M185L protein structure showed a slight change in the chemical bond in two zinc finger structures. Combined clinical data indicate that the mutation group had higher levels of total bile acid (TBA) than the wild-type group. Therefore, we hypothesized that these two mutations altered the protein structure of NR1H4, which impaired the function of NR1H4 itself and its target gene and caused an increase in TBA. Conclusions To our knowledge, this is the first study to identify the novel p.S145F and p.M185L mutations in 197 ICP patients. Our present study provides new insights into the genetic architecture of ICP involving the two novel NR1H4 mutations. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-022-01240-w.
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Affiliation(s)
- Hua Lai
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.,Department of Obstetrics, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Xianxian Liu
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.,Central Lab, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Siming Xin
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.,Department of Obstetrics, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Jiusheng Zheng
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.,Department of Obstetrics, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Huai Liu
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.,Department of Obstetrics, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Yu Ouyang
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.,Department of Obstetrics, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Huoxiu Yang
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.,Department of Obstetrics, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Yang Zeng
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.,Central Lab, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China
| | - Yang Zou
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China. .,Central Lab, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.
| | - Xiaoming Zeng
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China. .,Department of Obstetrics, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, 330006, Jiangxi, China.
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Tao J, Yu XL, Yuan YJ, Shen X, Liu J, Gu PP, Wang Z, Ma YT, Li GQ. DMRT2 Interacts With FXR and Improves Insulin Resistance in Adipocytes and a Mouse Model. Front Endocrinol (Lausanne) 2022; 12:723623. [PMID: 35250844 PMCID: PMC8891600 DOI: 10.3389/fendo.2021.723623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 12/28/2021] [Indexed: 11/17/2022] Open
Abstract
Insulin resistance (IR) plays a critical role in cardiovascular diseases and metabolic diseases. In this study, we identified the downregulation of DMRT2 in adipose tissues from insulin-resistant subjects through bioinformatics analysis and in an insulin-resistant mouse model through experimental analysis. DMRT2 overexpression significantly attenuated HDF-induced insulin resistance and inflammation in mice. Moreover, in control and insulin-resistant differentiated mouse 3T3-L1 adipocytes, DMRT2 overexpression attenuated but DMRT2 knockdown enhanced the insulin resistance of 3T3-L1 adipocytes. DMRT2 interacted with FXR and positively regulated FXR level and transcription activity. In both control and insulin-resistant differentiated mouse 3T3-L1 adipocytes, FXR knockdown enhanced the insulin resistance and attenuated the effects of DMRT2 overexpression upon 3T3-L1 adipocyte insulin resistance. In conclusion, we identify the downregulation of DMRT2 in the insulin-resistant mouse model and cell model. DMRT2 interacts with FXR and improves insulin resistance in adipocytes.
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Affiliation(s)
- Jing Tao
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Xiao-Lin Yu
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- Graduate School of Xinjiang Medical University, Urumqi, China
| | - Yu-Juan Yuan
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Graduate School of Xinjiang Medical University, Urumqi, China
| | - Xin Shen
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Jun Liu
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Pei-Pei Gu
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Zhao Wang
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Yi-Tong Ma
- Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Guo-Qing Li
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
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Feng H, Hu Y, Zhou S, Lu Y. Farnesoid X receptor contributes to oleanolic acid‐induced cholestatic liver injury in mice. J Appl Toxicol 2022; 42:1323-1336. [PMID: 35128688 PMCID: PMC9546401 DOI: 10.1002/jat.4298] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 01/20/2022] [Accepted: 02/01/2022] [Indexed: 11/13/2022]
Abstract
Farnesoid X receptor (FXR) is a nuclear receptor involved in the metabolism of bile acid. However, the molecular signaling of FXR in bile acid homeostasis in cholestatic drug‐induced liver injury remains unclear. Oleanolic acid (OA), a natural triterpenoid, has been reported to produce evident cholestatic liver injury in mice after a long‐term use. The present study aimed to investigate the role of FXR in OA‐induced cholestatic liver injury in mice using C57BL/6J (WT) mice and FXR knockout (FXR−/−) mice. The results showed that a significant alleviation in OA‐induced cholestatic liver injury was observed in FXR−/− mice as evidenced by decreases in serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase as well as reduced hepatocyte necrosis. UPLC‐MS analysis of bile acids revealed that the contents of bile acids decreased significantly in liver and serum, while increased in the bile in FXR−/− mice compared with in WT mice. In addition, the mRNA expressions of hepatic transporter Bsep, bile acid synthesis enzymes Bacs and Baat, and bile acids detoxifying enzymes Cyp3a11, Cyp2b10, Ephx1, Ugt1a1, and Ugt2b5 were increased in liver tissues of FXR−/− mice treated with OA. Furthermore, the expression of membrane protein BSEP was significantly higher in livers of FXR−/− mice compared with WT mice treated with OA. These results demonstrate that knockout of FXR may alleviate OA‐induced cholestatic liver injury in mice by decreasing accumulation of bile acids both in the liver and serum, increasing the export of bile acids via the bile, and by upregulation of bile acids detoxification enzymes. Oleanolic acid (OA) induces cholestatic liver injury in mice after a long‐term use. Here we demonstrated a significant alleviation in OA‐induced cholestatic liver injury in Farnesoid X receptor (FXR) knockout (FXR‐/‐) mice as compared to the wildtype mice. Downregulation of FXR decreased contents of bile acids in liver and serum, while increased the contents in the bile. In addition, the expression of membrane protein BSEP was significantly higher in livers of FXR‐/‐ mice compared to WT mice treated with OA.
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Affiliation(s)
- Hong Feng
- People’s Hospital of Zunyi City Bo Zhou District Zunyi Guizhou China
- Key Laboratory of Basic Pharmacology of the Ministry of Education and Joint International Research Laboratory of Ethnomedicine of the Ministry of Education Zunyi Medical University Zunyi Guizhou China
| | - Yan Hu
- Key Laboratory of Basic Pharmacology of the Ministry of Education and Joint International Research Laboratory of Ethnomedicine of the Ministry of Education Zunyi Medical University Zunyi Guizhou China
| | - Shaoyu Zhou
- Key Laboratory of Basic Pharmacology of the Ministry of Education and Joint International Research Laboratory of Ethnomedicine of the Ministry of Education Zunyi Medical University Zunyi Guizhou China
| | - Yuanfu Lu
- Key Laboratory of Basic Pharmacology of the Ministry of Education and Joint International Research Laboratory of Ethnomedicine of the Ministry of Education Zunyi Medical University Zunyi Guizhou China
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El Kasmi KC, Ghosh S, Anderson AL, Devereaux MW, Balasubramaniyan N, D'Alessandro A, Orlicky DJ, Suchy FJ, Shearn CT, Sokol RJ. Pharmacologic activation of hepatic farnesoid X receptor prevents parenteral nutrition-associated cholestasis in mice. Hepatology 2022; 75:252-265. [PMID: 34387888 DOI: 10.1002/hep.32101] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 07/13/2021] [Accepted: 07/26/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Parenteral nutrition (PN)-associated cholestasis (PNAC) complicates the care of patients with intestinal failure. In PNAC, phytosterol containing PN synergizes with intestinal injury and IL-1β derived from activated hepatic macrophages to suppress hepatocyte farnesoid X receptor (FXR) signaling and promote PNAC. We hypothesized that pharmacological activation of FXR would prevent PNAC in a mouse model. APPROACH AND RESULTS To induce PNAC, male C57BL/6 mice were subjected to intestinal injury (2% dextran sulfate sodium [DSS] for 4 days) followed by central venous catheterization and 14-day infusion of PN with or without the FXR agonist GW4064. Following sacrifice, hepatocellular injury, inflammation, and biliary and sterol transporter expression were determined. GW4064 (30 mg/kg/day) added to PN on days 4-14 prevented hepatic injury and cholestasis; reversed the suppressed mRNA expression of nuclear receptor subfamily 1, group H, member 4 (Nr1h4)/FXR, ATP-binding cassette subfamily B member 11 (Abcb11)/bile salt export pump, ATP-binding cassette subfamily C member 2 (Abcc2), ATP binding cassette subfamily B member 4(Abcb4), and ATP-binding cassette subfamily G members 5/8(Abcg5/8); and normalized serum bile acids. Chromatin immunoprecipitation of liver showed that GW4064 increased FXR binding to the Abcb11 promoter. Furthermore, GW4064 prevented DSS-PN-induced hepatic macrophage accumulation, hepatic expression of genes associated with macrophage recruitment and activation (ll-1b, C-C motif chemokine receptor 2, integrin subunit alpha M, lymphocyte antigen 6 complex locus C), and hepatic macrophage cytokine transcription in response to lipopolysaccharide in vitro. In primary mouse hepatocytes, GW4064 activated transcription of FXR canonical targets, irrespective of IL-1β exposure. Intestinal inflammation and ileal mRNAs (Nr1h4, Fgf15, and organic solute transporter alpha) were not different among groups, supporting a liver-specific effect of GW4064 in this model. CONCLUSIONS GW4064 prevents PNAC in mice through restoration of hepatic FXR signaling, resulting in increased expression of canalicular bile and of sterol and phospholipid transporters and suppression of macrophage recruitment and activation. These data support augmenting FXR activity as a therapeutic strategy to alleviate or prevent PNAC.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism
- ATP Binding Cassette Transporter, Subfamily G, Member 5/genetics
- ATP Binding Cassette Transporter, Subfamily G, Member 8/genetics
- Animals
- Bile Acids and Salts/blood
- Cholestasis/etiology
- Cholestasis/prevention & control
- Gene Expression/drug effects
- Gene Expression Regulation/drug effects
- Hepatocytes/metabolism
- Interleukin-1beta/pharmacology
- Intestinal Diseases/chemically induced
- Intestinal Diseases/therapy
- Isoxazoles/pharmacology
- Isoxazoles/therapeutic use
- Lipoproteins/genetics
- Liver Diseases/etiology
- Liver Diseases/pathology
- Liver Diseases/prevention & control
- Macrophage Activation/drug effects
- Macrophages/pathology
- Male
- Mice
- Mice, Inbred C57BL
- Multidrug Resistance-Associated Protein 2/genetics
- Multidrug Resistance-Associated Proteins/genetics
- Parenteral Nutrition/adverse effects
- RNA, Messenger/metabolism
- Receptors, Cytoplasmic and Nuclear/agonists
- Receptors, Cytoplasmic and Nuclear/genetics
- Receptors, Cytoplasmic and Nuclear/metabolism
- Signal Transduction/drug effects
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Affiliation(s)
- Karim C El Kasmi
- Section of Pediatric Gastroenterology, Hepatology and NutritionDepartment of PediatricsUniversity of Colorado School of MedicineAuroraColoradoUSA
- Pediatric Liver CenterDigestive Health InstituteChildren's Hospital ColoradoAuroraColoradoUSA
- Boehringer IngelheimIngelheim am RheinGermany
| | - Swati Ghosh
- Section of Pediatric Gastroenterology, Hepatology and NutritionDepartment of PediatricsUniversity of Colorado School of MedicineAuroraColoradoUSA
- Pediatric Liver CenterDigestive Health InstituteChildren's Hospital ColoradoAuroraColoradoUSA
| | - Aimee L Anderson
- Section of Pediatric Gastroenterology, Hepatology and NutritionDepartment of PediatricsUniversity of Colorado School of MedicineAuroraColoradoUSA
- Pediatric Liver CenterDigestive Health InstituteChildren's Hospital ColoradoAuroraColoradoUSA
| | - Michael W Devereaux
- Section of Pediatric Gastroenterology, Hepatology and NutritionDepartment of PediatricsUniversity of Colorado School of MedicineAuroraColoradoUSA
- Pediatric Liver CenterDigestive Health InstituteChildren's Hospital ColoradoAuroraColoradoUSA
| | - Natarajan Balasubramaniyan
- Section of Pediatric Gastroenterology, Hepatology and NutritionDepartment of PediatricsUniversity of Colorado School of MedicineAuroraColoradoUSA
- Pediatric Liver CenterDigestive Health InstituteChildren's Hospital ColoradoAuroraColoradoUSA
| | - Angelo D'Alessandro
- Department of Biochemistry and Molecular GeneticsUniversity of Colorado School of MedicineAuroraColoradoUSA
| | - David J Orlicky
- Department of PathologyUniversity of Colorado School of MedicineAuroraColoradoUSA
| | - Frederick J Suchy
- Section of Pediatric Gastroenterology, Hepatology and NutritionDepartment of PediatricsUniversity of Colorado School of MedicineAuroraColoradoUSA
- Pediatric Liver CenterDigestive Health InstituteChildren's Hospital ColoradoAuroraColoradoUSA
| | - Colin T Shearn
- Section of Pediatric Gastroenterology, Hepatology and NutritionDepartment of PediatricsUniversity of Colorado School of MedicineAuroraColoradoUSA
- Pediatric Liver CenterDigestive Health InstituteChildren's Hospital ColoradoAuroraColoradoUSA
| | - Ronald J Sokol
- Section of Pediatric Gastroenterology, Hepatology and NutritionDepartment of PediatricsUniversity of Colorado School of MedicineAuroraColoradoUSA
- Pediatric Liver CenterDigestive Health InstituteChildren's Hospital ColoradoAuroraColoradoUSA
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Zhang S, Hong F, Ma C, Yang S. Hepatic Lipid Metabolism Disorder and Atherosclerosis. Endocr Metab Immune Disord Drug Targets 2021; 22:590-600. [PMID: 34931971 DOI: 10.2174/1871530322666211220110810] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/28/2021] [Accepted: 11/01/2021] [Indexed: 11/22/2022]
Abstract
Lipid metabolism disorder plays a fundamental role in the pathogenesis of atherosclerosis. As the largest metabolic organ of the human body, liver has a key role in lipid metabolism by influencing fat production, fat decomposition, and the intake and secretion of serum lipoproteins. Numerous clinical and experimental studies have indicated that the dysfunction of hepatic lipid metabolism is closely tied to the onset of atherosclerosis. However, the identity and functional role of hepatic lipid metabolism responsible for these associations remain unknown. This review presented that cholesterol synthesis, cholesterol transport, and the metabolism of triglyceride, lipoproteins, and fatty acids are all associated with hepatic lipid metabolism and atherosclerosis. Moreover, we also discussed the roles of gut microbiota, inflammatory response, and oxidative stress in the pathological association between hepatic lipid metabolism and atherosclerosis. These significant evidences support strongly that hepatic lipid metabolism disorders may increase the risk of atherosclerosis.
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Affiliation(s)
- Sen Zhang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang, China
| | - Fenfang Hong
- Experimental Center of Pathogen Biology, Nanchang University, Nanchang, China
| | - Chen Ma
- Department of Physiology, College of Medicine, Nanchang University, Nanchang, China
| | - Shulong Yang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang, China
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Cao X, Ren S, Cai C, Ni Q, Li X, Meng Y, Meng Z, Shi Y, Chen H, Jiang R, Wu P, Ye Y. Dietary pectin caused great changes in bile acid profiles of Pelteobagrus fulvidraco. FISH PHYSIOLOGY AND BIOCHEMISTRY 2021; 47:2015-2025. [PMID: 34709495 DOI: 10.1007/s10695-021-01028-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 10/13/2021] [Indexed: 06/13/2023]
Abstract
To reveal the impact of dietary fiber (DF) on the bile acid (BA) profiles of fish, yellow catfish (Pelteobagrus fulvidraco) were fed a diet containing 300 g kg-1 dextrin (CON diet, control) or pectin (a type of soluble DF, PEC diet) for 7 days, and then the BA profiles were analyzed by UHPLC-MS/MS. A total of 26 individuals of BAs were detected in the fish body, with 8, 10, 14, and 22 individuals of BAs detected in the liver, serum, bile, and hindgut digesta, respectively. The conjugated BAs (CBAs) of fish were dominated by taurine CBAs (TCBAs). The concentrations of free BAs (FBAs) and the value of FBAs/CBAs in the bile of fish fed the PEC diet were nearly 5 and 7 times higher, respectively than those in fish fed the CON diet. The value of glycine CBAs/TCBAs in the liver, serum and bile of fish fed the PEC diet was significantly lower, and in the hindgut digesta was higher than that of fish fed the CON diet (P < 0.05). These results suggested that dietary pectin greatly changed the BA profiles of Pelteobagrus fulvidraco, attributed to inhibition of reabsorption of BAs. Therefore, attention should be paid to the impact on BA homeostasis when replacing fishmeal with DF-rich plant ingredients in the fish diet.
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Affiliation(s)
- Xiamin Cao
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China.
| | - Shengjie Ren
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China
| | - Chunfang Cai
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China.
| | - Qin Ni
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China
| | - Xinyue Li
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China
| | - Yunhe Meng
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China
| | - Zijing Meng
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China
| | - Ye Shi
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China
| | - Huangen Chen
- Jiangsu Fisheries Technology Promotion Center, Nanjing, 210036, People's Republic of China
| | - Rong Jiang
- Wuxi Sanzhi Biotech Co., Ltd, Wuxi, 214101, People's Republic of China
| | - Ping Wu
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China
| | - Yuantu Ye
- School of Basic Medicine and Biological Science, Soochow University, Suzhou, 215123, People's Republic of China
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Ghosh S, Devereaux MW, Anderson AL, Gehrke S, Reisz JA, D’Alessandro A, Orlicky DJ, Lovell M, El Kasmi KC, Shearn CT, Sokol RJ. NF-κB Regulation of LRH-1 and ABCG5/8 Potentiates Phytosterol Role in the Pathogenesis of Parenteral Nutrition-Associated Cholestasis. Hepatology 2021; 74:3284-3300. [PMID: 34310734 PMCID: PMC8639620 DOI: 10.1002/hep.32071] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 06/30/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Chronically administered parenteral nutrition (PN) in patients with intestinal failure carries the risk for developing PN-associated cholestasis (PNAC). We have demonstrated that farnesoid X receptor (FXR) and liver X receptor (LXR), proinflammatory interleukin-1 beta (IL-1β), and infused phytosterols are important in murine PNAC pathogenesis. In this study we examined the role of nuclear receptor liver receptor homolog 1 (LRH-1) and phytosterols in PNAC. APPROACH AND RESULTS In a C57BL/6 PNAC mouse model (dextran sulfate sodium [DSS] pretreatment followed by 14 days of PN; DSS-PN), hepatic nuclear receptor subfamily 5, group A, member 2/LRH-1 mRNA, LRH-1 protein expression, and binding of LRH-1 at the Abcg5/8 and Cyp7a1 promoter was reduced. Interleukin-1 receptor-deficient mice (Il-1r-/- /DSS-PN) were protected from PNAC and had significantly increased hepatic mRNA and protein expression of LRH-1. NF-κB activation and binding to the LRH-1 promoter were increased in DSS-PN PNAC mice and normalized in Il-1r-/- /DSS-PN mice. Knockdown of NF-κB in IL-1β-exposed HepG2 cells increased expression of LRH-1 and ABCG5. Treatment of HepG2 cells and primary mouse hepatocytes with an LRH-1 inverse agonist, ML179, significantly reduced mRNA expression of FXR targets ATP binding cassette subfamily C member 2/multidrug resistance associated protein 2 (ABCC2/MRP2), nuclear receptor subfamily 0, groupB, member 2/small heterodimer partner (NR0B2/SHP), and ATP binding cassette subfamily B member 11/bile salt export pump (ABCB11/BSEP). Co-incubation with phytosterols further reduced expression of these genes. Similar results were obtained by suppressing the LRH-1 targets ABCG5/8 by treatment with small interfering RNA, IL-1β, or LXR antagonist GSK2033. Liquid chromatography-mass spectrometry and chromatin immunoprecipitation experiments in HepG2 cells showed that ATP binding cassette subfamily G member 5/8 (ABCG5/8) suppression by GSK2033 increased the accumulation of phytosterols and reduced binding of FXR to the SHP promoter. Finally, treatment with LRH-1 agonist, dilauroyl phosphatidylcholine (DLPC) protected DSS-PN mice from PNAC. CONCLUSIONS This study suggests that NF-κB regulation of LRH-1 and downstream genes may affect phytosterol-mediated antagonism of FXR signaling in the pathogenesis of PNAC. LRH-1 could be a potential therapeutic target for PNAC.
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Affiliation(s)
- Swati Ghosh
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO,Pediatric Liver Center, Digestive Health Institute, Children’s Hospital Colorado, Aurora, CO
| | - Michael W. Devereaux
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO,Pediatric Liver Center, Digestive Health Institute, Children’s Hospital Colorado, Aurora, CO
| | - Aimee L. Anderson
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO,Pediatric Liver Center, Digestive Health Institute, Children’s Hospital Colorado, Aurora, CO
| | - Sarah Gehrke
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO
| | - Julie A. Reisz
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO
| | - Angelo D’Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO
| | - David J. Orlicky
- Department of Pathology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO
| | - Mark Lovell
- Department of Pathology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO,Department of Pathology, Children’s Hospital Colorado, Aurora, CO
| | - Karim C. El Kasmi
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - Colin T. Shearn
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - Ronald J. Sokol
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO,Pediatric Liver Center, Digestive Health Institute, Children’s Hospital Colorado, Aurora, CO
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Ren T, Pang L, Dai W, Wu S, Kong J. Regulatory mechanisms of the bile salt export pump (BSEP/ABCB11) and its role in related diseases. Clin Res Hepatol Gastroenterol 2021; 45:101641. [PMID: 33581308 DOI: 10.1016/j.clinre.2021.101641] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 01/03/2021] [Accepted: 01/21/2021] [Indexed: 02/04/2023]
Abstract
The bile salt export pump (BSEP/ABCB11) is located on the apical membrane and mediates the secretion of bile salts from hepatocytes into the bile. BSEP-mediated bile salt efflux is the rate-limiting step of bile salt secretion and the main driving force of bile flow. BSEP drives and maintains the enterohepatic circulation of bile salts. In recent years, research efforts have been focused on understanding the physiological and pathological functions and regulatory mechanisms of BSEP. These studies elucidated the roles of farnesoid X receptor (FXR), AMP-activated protein kinase (AMPK), liver receptor homolog-1(LRH-1) and nuclear factor erythroid 2-related factor 2 (Nrf-2) in BSEP expression and discovered some regulatory factors which participate in its post-transcriptional regulation. A series of liver diseases have also been shown to be related to BSEP expression and dysfunction, such as cholestasis, drug-induced liver injury, and gallstones. Here, we systematically review and summarize recent literature on BSEP structure, physiological functions, regulatory mechanisms, and related diseases.
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Affiliation(s)
- Tengqi Ren
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Liwei Pang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wanlin Dai
- Innovation Institute of China Medical University, Shenyang, Liaoning, China
| | - Shuodong Wu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jing Kong
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
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Zhang K, Yao Y, Wang M, Liu F, Wang Q, Ma H, Xie Y, Ma Y, Dai P, Zhu C, Lin C. A UPLC-MS/MS-based metabolomics analysis of the pharmacological mechanisms of rabdosia serra against cholestasis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 91:153683. [PMID: 34364160 DOI: 10.1016/j.phymed.2021.153683] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 07/14/2021] [Accepted: 07/16/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Rabdosia Serra, the dried aerial parts of Rabdosia serra (Maxim.) Hara (RS) from the Labiatae family, is a traditional Chinese herbal medicine called Xihuangcao. Although RS has been found to exert a therapeutic effect on cholestasis, the underlying molecular mechanism remains unclear. PURPOSE This study was designed to investigate the pharmacological effect and mechanism of RS on cholestatic rats using metabolomics platform. METHODS Histopathology and biochemical evaluations were performed to determine the therapeutic effect of RS and developed a rapid metabolite detection technology method based on UPLC-MS/MS to perform metabolomics research. Further, quantitative real-time polymerase chain reaction (RT-qPCR) was used to study the effect of RS on the bile acid metabolism pathway at the transcriptional level. RESULTS RS significantly reduced the bile flow rates in cholestatic rats and decreased the levels of ALT, AST, TBA, T-BIL, and LDH, which were increased in the model group. Histological analysis showed that RS alleviated the liver injury induced by ANIT. Serum metabolomics results revealed 33 of the 37 biomarkers were found to be significantly altered by ANIT, and 26 were considerably changed following treatment with RS. Metabolic pathway analysis revealed four pathways such as primary bile acid biosynthesis, biosynthesis of unsaturated fatty acids, and arachidonic acid and tryptophan metabolism. The bile acid secretion process and the inflammation and oxidative stress processes are the major biochemical reactions following treatment with ANIT and RS. Bile acid-targeted metabolomics study showed that TCA, GCA, GCDCA, and GDCA might be sensitive biomarkers that induced liver injury. we found that treatment with RS regulated the levels of bile acid in the serum and liver and restored the proportion of bile acids, especially CA and conjugated bile acids, such as TCA and GCA, in the bile duct. RS increased the mRNA expression levels of FXR, SHP, BSEP, and MRP2 in livers, and IBABP, OST-α, and OST-β in the ileum. CONCLUSION In this study, RS was found to protect the liver by regulating multiple metabolic pathways and promoting the excretion of bile acids. Simultaneously, RS played an essential role in reversing the imbalance of bile acids and protected against cholestasis by regulating the expression of transporters associated with bile acids. We demonstrated the correlation between molecular mechanisms and metabolites, provide a reference for the fabrication of extracts that can be used to treat cholestasis.
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Affiliation(s)
- Kaihui Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Yufeng Yao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Meiqi Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Fangle Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Qian Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Huanhuan Ma
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Yuanyuan Xie
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Yunxia Ma
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Pengyu Dai
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Chenchen Zhu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China.
| | - Chaozhan Lin
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China.
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Petrescu AD, DeMorrow S. Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury. Cells 2021; 10:cells10081846. [PMID: 34440614 PMCID: PMC8392259 DOI: 10.3390/cells10081846] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/16/2021] [Accepted: 07/17/2021] [Indexed: 02/06/2023] Open
Abstract
Recent studies on liver disease burden worldwide estimated that cirrhosis is the 11th most common cause of death globally, and there is a great need for new therapies to limit the progression of liver injuries in the early stages. Cholestasis is caused by accumulation of hydrophobic bile acids (BA) in the liver due to dysfunctional BA efflux or bile flow into the gall bladder. Therefore, strategies to increase detoxification of hydrophobic BA and downregulate genes involved in BA production are largely investigated. Farnesoid X receptor (FXR) has a central role in BA homeostasis and recent publications revealed that changes in autophagy due to BA-induced reactive oxygen species and increased anti-oxidant response via nuclear factor E2-related factor 2 (NRF2), result in dysregulation of FXR signaling. Several mechanistic studies have identified new dysfunctions of the cholestatic liver at cellular and molecular level, opening new venues for developing more performant therapies.
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Affiliation(s)
- Anca D. Petrescu
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA;
- Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA
| | - Sharon DeMorrow
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA;
- Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA
- Central Texas Veterans Health Care System, Temple, TX 78712, USA
- Correspondence: ; Tel.: +1-512-495-5779
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Wen J, Mercado GP, Volland A, Doden HL, Lickwar CR, Crooks T, Kakiyama G, Kelly C, Cocchiaro JL, Ridlon JM, Rawls JF. Fxr signaling and microbial metabolism of bile salts in the zebrafish intestine. SCIENCE ADVANCES 2021; 7:eabg1371. [PMID: 34301599 PMCID: PMC8302129 DOI: 10.1126/sciadv.abg1371] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 06/07/2021] [Indexed: 05/02/2023]
Abstract
Bile salt synthesis, secretion into the intestinal lumen, and resorption in the ileum occur in all vertebrate classes. In mammals, bile salt composition is determined by host and microbial enzymes, affecting signaling through the bile salt-binding transcription factor farnesoid X receptor (Fxr). However, these processes in other vertebrate classes remain poorly understood. We show that key components of hepatic bile salt synthesis and ileal transport pathways are conserved and under control of Fxr in zebrafish. Zebrafish bile salts consist primarily of a C27 bile alcohol and a C24 bile acid that undergo multiple microbial modifications including bile acid deconjugation that augments Fxr activity. Using single-cell RNA sequencing, we provide a cellular atlas of the zebrafish intestinal epithelium and uncover roles for Fxr in transcriptional and differentiation programs in ileal and other cell types. These results establish zebrafish as a nonmammalian vertebrate model for studying bile salt metabolism and Fxr signaling.
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Affiliation(s)
- Jia Wen
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Gilberto Padilla Mercado
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Alyssa Volland
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana Champaign, Urbana, IL, USA
| | - Heidi L Doden
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana Champaign, Urbana, IL, USA
- Department of Animal Sciences, University of Illinois at Urbana Champaign, Urbana, IL, USA
| | - Colin R Lickwar
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Taylor Crooks
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana Champaign, Urbana, IL, USA
| | - Genta Kakiyama
- Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Cecelia Kelly
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Jordan L Cocchiaro
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Jason M Ridlon
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana Champaign, Urbana, IL, USA.
- Department of Animal Sciences, University of Illinois at Urbana Champaign, Urbana, IL, USA
- Division of Nutritional Sciences, University of Illinois at Urbana Champaign, Urbana, IL, USA
- Cancer Center of Illinois, Urbana, IL, USA
| | - John F Rawls
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA.
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Ahn IS, Yoon J, Diamante G, Cohn P, Jang C, Yang X. Disparate Metabolomic Responses to Fructose Consumption between Different Mouse Strains and the Role of Gut Microbiota. Metabolites 2021; 11:metabo11060342. [PMID: 34073358 PMCID: PMC8228112 DOI: 10.3390/metabo11060342] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/20/2021] [Accepted: 05/24/2021] [Indexed: 01/14/2023] Open
Abstract
High fructose consumption has been linked to metabolic syndrome, yet the fructose-induced phenotypes, gene expression, and gut microbiota alterations are distinct between mouse strains. In this study, we aim to investigate how fructose consumption shapes the metabolomic profiles of mice with different genetic background and microbiome. We used fructose-sensitive DBA/2J (DBA) and fructose-resistant C57BL/6J (B6) mice given 8% fructose or regular water for 12 weeks. Plasma and fecal metabolites were profiled using a liquid chromatography-tandem mass spectrometry based global metabolomic approach. We found that the baseline metabolomic profiles were different between DBA and B6 mice, particularly plasma metabolites involved in lipid metabolism and fecal metabolites related to dipeptide/amino acid metabolism. In response to fructose, DBA mice showed a distinct decrease of plasma branched chain fatty acids with concordantly increased branched chain amino acids, which were correlated with adiposity; B6 mice had significantly increased plasma cholesterol and total bile acids, accompanied by decreased fecal levels of farnesoid X receptor antagonist tauro-β-muricholate, which were correlated with fructose-responsive bacteria Dehalobacterium, Magibacteriaceae, and/or Akkermansia. Our results demonstrate that baseline metabolomic profiles differ and respond differentially to fructose between mice with different genetic background and gut microbiota, which may play a role in individualized risks to fructose-induced metabolic syndrome.
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Affiliation(s)
- In-Sook Ahn
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, USA; (I.-S.A.); (J.Y.); (G.D.); (P.C.)
| | - Justin Yoon
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, USA; (I.-S.A.); (J.Y.); (G.D.); (P.C.)
| | - Graciel Diamante
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, USA; (I.-S.A.); (J.Y.); (G.D.); (P.C.)
| | - Peter Cohn
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, USA; (I.-S.A.); (J.Y.); (G.D.); (P.C.)
| | - Cholsoon Jang
- Department of Biological Chemistry, University of California, Irvine, CA 92697, USA;
| | - Xia Yang
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, USA; (I.-S.A.); (J.Y.); (G.D.); (P.C.)
- Brain Research Institute, University of California, Los Angeles, CA 90095, USA
- Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA
- Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA 90095, USA
- Correspondence: ; Tel.: +1-310-206-1812
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Gasaly N, de Vos P, Hermoso MA. Impact of Bacterial Metabolites on Gut Barrier Function and Host Immunity: A Focus on Bacterial Metabolism and Its Relevance for Intestinal Inflammation. Front Immunol 2021; 12:658354. [PMID: 34122415 PMCID: PMC8187770 DOI: 10.3389/fimmu.2021.658354] [Citation(s) in RCA: 280] [Impact Index Per Article: 70.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 04/29/2021] [Indexed: 12/13/2022] Open
Abstract
The diverse and dynamic microbial community of the human gastrointestinal tract plays a vital role in health, with gut microbiota supporting the development and function of the gut immune barrier. Crosstalk between microbiota-gut epithelium and the gut immune system determine the individual health status, and any crosstalk disturbance may lead to chronic intestinal conditions, such as inflammatory bowel diseases (IBD) and celiac disease. Microbiota-derived metabolites are crucial mediators of host-microbial interactions. Some beneficially affect host physiology such as short-chain fatty acids (SCFAs) and secondary bile acids. Also, tryptophan catabolites determine immune responses, such as through binding to the aryl hydrocarbon receptor (AhR). AhR is abundantly present at mucosal surfaces and when activated enhances intestinal epithelial barrier function as well as regulatory immune responses. Exogenous diet-derived indoles (tryptophan) are a major source of endogenous AhR ligand precursors and together with SCFAs and secondary bile acids regulate inflammation by lowering stress in epithelium and gut immunity, and in IBD, AhR expression is downregulated together with tryptophan metabolites. Here, we present an overview of host microbiota-epithelium- gut immunity crosstalk and review how microbial-derived metabolites contribute to host immune homeostasis. Also, we discuss the therapeutic potential of bacterial catabolites for IBD and celiac disease and how essential dietary components such as dietary fibers and bacterial tryptophan catabolites may contribute to intestinal and systemic homeostasis.
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Affiliation(s)
- Naschla Gasaly
- Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Paul de Vos
- Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, Netherlands
| | - Marcela A Hermoso
- Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago, Chile
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Wang M, Liu F, Yao Y, Zhang Q, Lu Z, Zhang R, Liu C, Lin C, Zhu C. Network pharmacology-based mechanism prediction and pharmacological validation of Xiaoyan Lidan formula on attenuating alpha-naphthylisothiocyanate induced cholestatic hepatic injury in rats. JOURNAL OF ETHNOPHARMACOLOGY 2021; 270:113816. [PMID: 33444723 DOI: 10.1016/j.jep.2021.113816] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 01/04/2021] [Accepted: 01/06/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The well-known Chinese prescription, Xiaoyan Lidan Formula (XYLDF), possesses efficiency of heat-clearing, dampness-eliminating and jaundice-removing. It has long been used clinically for the treatment of hepatobiliary diseases due to intrahepatic cholestasis (IHC). However, the mechanism of XYLDF for its therapeutic effects remains elusive. AIM OF THE STUDY The study aimed to explore the potential targets for liver protective mechanism of XYLDF based on network pharmacology and experimental assays in ANIT-induced cholestatic hepatic injury (CHI) in rats. MATERIALS AND METHODS On the basis of the 29 serum migrant compounds of XYLDF elucidated by UPLC-TOF-MS/MS, a network pharmacology approach was applied for the mechanism prediction. Systematic networks were constructed to identify potential molecular targets, biological processes, and signaling pathways. And the interactions between significantly potential targets and active compounds were simulated by molecular docking. For the mechanism validation, an ANIT-induced rat model was used to evaluate the effects of XYLDF on CHI according to serum biochemistry, bile flow rates, histopathological examination, and the gene and protein expression including enzymes related to synthesis, export, and import of bile acid in liver and ileum, and those of inflammatory cytokines, analyzed by RT-qPCR and WB. RESULTS The results of network pharmacology research indicated TNF (TNF-α), RELA (NF-κB), NR1H4 (FXR), and ICAM1 (ICAM-1) to be the important potential targets of XYLDF for cholestatic liver injury, which are related to bile metabolism and NF-κB-mediated inflammatory signaling. And the molecular docking had pre-validated the prediction of network pharmacology, as the core active compounds of XYLDF had shown strong simulation binding affinity with FXR, followed by NF-κB, TNF-α, and ICAM-1. Meanwhile, the effects of XYLDF after oral administration on ANIT-induced CHI in rats exhibited the decreased levels of transaminases (ALT and AST), TBA, and TBIL in serum, raised bile flow rates, and markedly improved hepatic histopathology. Furthermore, consistent to the above targets prediction and molecular docking, XYLDF significantly up-regulated the expression of FXR, SHP, BSEP, and MRP2, and down-regulated CYP7A1 and NTCP in liver, and promoted expression of IBABP and OSTα/β in ileum, suggesting the activation of FXR-mediated pathway referring to bile acid synthesis, transportation, and reabsorption. Moreover, the lower levels of TNF-α in plasma and liver, as well as the reduced hepatic gene and protein expression of NF-κB, TNF-α, and ICAM-1 after XYLDF treatment revealed the suppression of NF-κB-mediated inflammatory signaling pathway, as evidenced by the inhibition of nuclear translocation of NF-κB. CONCLUSIONS XYLDF exhibited an ameliorative liver protective effect on ANIT-induced cholestatic hepatic injury. The present study has confirmed its mechanism as activating the FXR-regulated bile acid pathway and inhibiting inflammation via the NF-κB signaling pathway.
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MESH Headings
- 1-Naphthylisothiocyanate/toxicity
- Animals
- Bile Acids and Salts/metabolism
- Chemical and Drug Induced Liver Injury/blood
- Chemical and Drug Induced Liver Injury/drug therapy
- Chemical and Drug Induced Liver Injury/pathology
- Cholestasis, Intrahepatic/blood
- Cholestasis, Intrahepatic/chemically induced
- Cholestasis, Intrahepatic/drug therapy
- Cholestasis, Intrahepatic/pathology
- Disease Models, Animal
- Drugs, Chinese Herbal/pharmacology
- Drugs, Chinese Herbal/therapeutic use
- Inflammation/drug therapy
- Inflammation/metabolism
- Male
- Metabolic Networks and Pathways/drug effects
- Molecular Docking Simulation
- NF-kappa B/metabolism
- Protective Agents/pharmacology
- Protective Agents/therapeutic use
- Protein Interaction Maps/drug effects
- Rats, Sprague-Dawley
- Receptors, Cytoplasmic and Nuclear/chemistry
- Receptors, Cytoplasmic and Nuclear/metabolism
- Signal Transduction/drug effects
- Rats
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Affiliation(s)
- Meiqi Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Fangle Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Yufeng Yao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Qiuyu Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Zenghui Lu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Runjing Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Changhui Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Chaozhan Lin
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China.
| | - Chenchen Zhu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China.
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Bosma PJ, Wits M, Oude-Elferink RPJ. Gene Therapy for Progressive Familial Intrahepatic Cholestasis: Current Progress and Future Prospects. Int J Mol Sci 2020; 22:E273. [PMID: 33383947 PMCID: PMC7796371 DOI: 10.3390/ijms22010273] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/24/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Progressive Familial Intrahepatic Cholestasis (PFIC) are inherited severe liver disorders presenting early in life, with high serum bile salt and bilirubin levels. Six types have been reported, two of these are caused by deficiency of an ABC transporter; ABCB11 (bile salt export pump) in type 2; ABCB4 (phosphatidylcholine floppase) in type 3. In addition, ABCB11 function is affected in 3 other types of PFIC. A lack of effective treatment makes a liver transplantation necessary in most patients. In view of long-term adverse effects, for instance due to life-long immune suppression needed to prevent organ rejection, gene therapy could be a preferable approach, as supported by proof of concept in animal models for PFIC3. This review discusses the feasibility of gene therapy as an alternative for liver transplantation for all forms of PFIC based on their pathological mechanism. Conclusion: Using presently available gene therapy vectors, major hurdles need to be overcome to make gene therapy for all types of PFIC a reality.
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Affiliation(s)
- Piter J. Bosma
- Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, AGEM, Amsterdam UMC, University of Amsterdam, 1105 BK Amsterdam, The Netherlands; (M.W.); (R.P.J.O.-E.)
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Amirneni S, Haep N, Gad MA, Soto-Gutierrez A, Squires JE, Florentino RM. Molecular overview of progressive familial intrahepatic cholestasis. World J Gastroenterol 2020; 26:7470-7484. [PMID: 33384548 PMCID: PMC7754551 DOI: 10.3748/wjg.v26.i47.7470] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/05/2020] [Accepted: 11/29/2020] [Indexed: 02/06/2023] Open
Abstract
Cholestasis is a clinical condition resulting from the imapairment of bile flow. This condition could be caused by defects of the hepatocytes, which are responsible for the complex process of bile formation and secretion, and/or caused by defects in the secretory machinery of cholangiocytes. Several mutations and pathways that lead to cholestasis have been described. Progressive familial intrahepatic cholestasis (PFIC) is a group of rare diseases caused by autosomal recessive mutations in the genes that encode proteins expressed mainly in the apical membrane of the hepatocytes. PFIC 1, also known as Byler’s disease, is caused by mutations of the ATP8B1 gene, which encodes the familial intrahepatic cholestasis 1 protein. PFIC 2 is characterized by the downregulation or absence of functional bile salt export pump (BSEP) expression via variations in the ABCB11 gene. Mutations of the ABCB4 gene result in lower expression of the multidrug resistance class 3 glycoprotein, leading to the third type of PFIC. Newer variations of this disease have been described. Loss of function of the tight junction protein 2 protein results in PFIC 4, while mutations of the NR1H4 gene, which encodes farnesoid X receptor, an important transcription factor for bile formation, cause PFIC 5. A recently described type of PFIC is associated with a mutation in the MYO5B gene, important for the trafficking of BSEP and hepatocyte membrane polarization. In this review, we provide a brief overview of the molecular mechanisms and clinical features associated with each type of PFIC based on peer reviewed journals published between 1993 and 2020.
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Affiliation(s)
- Sriram Amirneni
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - Nils Haep
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - Mohammad A Gad
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - Alejandro Soto-Gutierrez
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, United States
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - James E Squires
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15213, United States
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Rodrigo M Florentino
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, United States
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The pharmacological activity of berberine, a review for liver protection. Eur J Pharmacol 2020; 890:173655. [PMID: 33068590 DOI: 10.1016/j.ejphar.2020.173655] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 10/06/2020] [Accepted: 10/13/2020] [Indexed: 12/14/2022]
Abstract
Liver plays an important role in bile synthesis, metabolic function, degradation of toxins, new substances synthesis in body. However, hepatopathy morbidity and mortality are increasing year by year around the world, which become a major public health problem. Traditional Chinese medicine (TCM) has a prominent role in the treatment of liver diseases due to its definite curative effect and small side effects. The hepatoprotective effect of berberine has been extensively studied, so we comprehensively summarize the pharmacological activities of lipid metabolism regulation, bile acid adjustment, anti-inflammation, oxidation resistance, anti-fibrosis and anti-cancer and so on. Besides, the metabolism and toxicity of berberine and its new formulations to improve its effectiveness are expounded, providing a reference for the safe and effective clinical use of berberine.
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Song J, Cui ZY, Lian LH, Han X, Hou LS, Wang G, Gao L, Zhu Y, Jiang YC, Dou JY, Hu ZH, Zhao YQ, Nan JX, Wu YL. 20 S-Protopanaxatriol Ameliorates Hepatic Fibrosis, Potentially Involving FXR-Mediated Inflammatory Signaling Cascades. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:8195-8204. [PMID: 32662640 DOI: 10.1021/acs.jafc.0c01978] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Ginseng has been used as a functional food and tonic for enhancing immune power. Here, the potential protective effect of 20S-protopanaxatriol (M4), the metabolite of protopanaxatriol, against hepatic fibrosis is investigated, which could provide nutritional interventions for disease treatment. M4 could inhibit extracellular matrix (ECM) deposition and reduce the levels of proinflammatory cytokines such as caspase 1, interleukin 1 β (IL-1β), interleukin 1 receptor type 1 (IL1R1), and interleukin 6 (IL-6). M4 also significantly increased the expression of farnesoid X receptor (FXR), suppressed the purinergic ligand-gated ion channel 7 receptor (P2X7r) signaling pathway, and works as an FXR agonist, GW4064. In thioacetamide (TAA)-induced mice, M4 could attenuate the histopathological changes and significantly regulate the expression levels of FXR and P2X7r. M4 ameliorated TAA-induced hepatic fibrosis due to the reduction of P2X7r secretion, inhibition of hepatic stellate cell (HSCs) activation, and inflammation, which were all associated with FXR activation. Hence, M4 might be useful a nutritional preventive approach in antihepatic fibrosis and antihepatic inflammation.
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Affiliation(s)
- Jian Song
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Zhen-Yu Cui
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Li-Hua Lian
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Xin Han
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Li-Shuang Hou
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Ge Wang
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Lu Gao
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Yue Zhu
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Yu-Chen Jiang
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Jia-Yi Dou
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Zhong-He Hu
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Yu-Qing Zhao
- Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Ji-Xing Nan
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
- Clinical Research Center, Affiliated Hospital of Yanbian University, Yanji, Jilin 133002, China
| | - Yan-Ling Wu
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
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Quantitative proteomics analysis of Fructus Psoraleae-induced hepatotoxicity in rats. Chin J Nat Med 2020; 18:123-137. [PMID: 32172948 DOI: 10.1016/s1875-5364(20)30013-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Indexed: 01/08/2023]
Abstract
Fructus Psoraleae, which is commonly consumed for the treatment of osteoporosis, bone fracture, and leucoderma, induces liver injury. This study investigated the pathogenesis of the ethanol extract of Fructus Psoraleae (EEFP)-induced liver injury in rats. EEFP (1.35, 1.80, and 2.25 g·kg-1) was administrated to Sprague Dawley (SD) rats for 30 d. We measured liver chemistries, histopathology, and quantitative isobaric tags for relative and absolute quantitation (iTRAQ)-based protein profiling. EEFP demonstrated parameters suggestive of liver injury with changes in bile secretion, bile flow rate, and liver histopathology. iTRAQ analysis showed that a total of 4042 proteins were expressed in liver tissues of EEFP-treated and untreated rats. Among these proteins, 81 were upregulated and 32 were downregulated in the treatment group. KEGG pathway analysis showed that the drug metabolic pathways of cytochrome P450, glutathione metabolism, glycerolipid metabolism, and bile secretion were enriched with differentially expressed proteins. The expression of key proteins related to the farnesoid X receptor (FXR), i.e., the peroxisome proliferators-activated receptor alpha (PPAR-α), were downregulated, and multidrug resistance-associated protein 3 (MRP3) was upregulated in the EEFP-treated rats. Our results provide evidence that EEFP may induce hepatotoxicity through various pathways. Furthermore, our study demonstrates changes in protein regulation using iTRAQ quantitative proteomics analysis.
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Wang H, Liu D, Ji Y, Liu Y, Xu L, Guo Y. Dietary Supplementation of Black Rice Anthocyanin Extract Regulates Cholesterol Metabolism and Improves Gut Microbiota Dysbiosis in C57BL/6J Mice Fed a High-Fat and Cholesterol Diet. Mol Nutr Food Res 2020; 64:e1900876. [PMID: 32050056 DOI: 10.1002/mnfr.201900876] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Revised: 12/23/2019] [Indexed: 12/19/2022]
Abstract
SCOPE This study explores the beneficial effects of dietary supplementation of black rice anthocyanin extract (BRAE) on cholesterol metabolism and gut dysbiosis. METHODS AND RESULTS C57BL/6J mice are grouped into the normal chow diet group (NCD), the high-fat and the cholesterol diet group (HCD), and three treatment groups feeding HCD supplemented with various dosage of BRAE for 12 weeks. Results reveal that BRAE alleviates the increased body weight, serum triglyceride (TG), total cholesterol (TC), non-high-density lipoprotein cholesterol levels (non-HDL-C), and increased fecal sterols excretion and caecal short-chain fatty acids (SCFAs) concentration in HCD-induced hypercholesterolemic mice. Moreover, BRAE decreases hepatic TC content through the fundamental regulation of body energy balance gene, adenosine 5'-monophosphate activated protein kinase α (AMPKα). Meanwhile, BRAE improves the genes expression involved in cholesterol uptake and efflux, and preserves CYP7A1, ATP-binding cassette subfamily G member 5/8 mRNA expression, and the relative abundance of gut microbiota. Additionally, the antibiotic treatment experiment indicates that the beneficial effects of BRAE in reducing hypocholesterolemia risk largely depends on the gut microbiota homeostasis. CONCLUSION BRAE supplement could be a beneficial treatment option for preventing HCD-induced hypocholesterolemia and related metabolic syndromes.
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Affiliation(s)
- Hao Wang
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology, Tianjin, 300457, China
| | - Dong Liu
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology, Tianjin, 300457, China
| | - Yanglin Ji
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology, Tianjin, 300457, China
| | - Yaojie Liu
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology, Tianjin, 300457, China
| | - Lin Xu
- Pathology Department, Tianjin Municipal Public Security Hospital, Tianjin, 300042, China
| | - Yatu Guo
- Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Hospital, Tianjin Eye Institute, Tianjin, 300384, China
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